3-cyano-2-pyrryl oxamic acids

ABSTRACT

THIS INVENTION RELATES TO NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAID COMPOUNDS OF THE FORMULA:   1-R3,2-(MO-CO-CO-NH-),3-(NC-),4-R1,5-R2-PYRROLE   WHEREIN M IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, ALUMINUM, AMMONIUM, SODIUM, POTASSIUM, CALCIUM, AND TRIS-(HYDROXYMETHYL)METHYLAMMONIUM, R1 IS SELECTED FROM THE GROUP CONSISTING OF LOWER ALKYL OF 1 THROUGH 6 CARBON ATOMS,   X-PHENYL   WHEREIN X IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, FLUORINE, CHLORINE, BROMINE, METHOXY, METHYL AND TRIFLUOROMETHYL, R2 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND LOWER ALKYL OF 1 THROUGH 6 CARBON ATOMS, AND R3 HAS THE SAME MEANING AS R1 AND IN ADDITION HYDROGEN. THE COMPOUNDS (1A) ABOVE ARE FORMULATED WITH PHARMACEUTICAL CARRIERS FOR INHALATION OR FOR ORAL, PARENTERAL OR RECTAL ADMINISTRATION, WITH INSUFFLATION BEING THE PREFERRED METHOD. THE COMPOSITONS ARE USEFUL IN THE PROPHYLACTIC TREATMENT OF SENSITIZED HUMANS AND MAMMALS FOR ALLERGIC AND ALL ANAPHYLACTIC REACTIONS OF A REAGIN-MEDIATED AND NON-REAGIN-MEDIATED NATURE.

ABSTRACT OF THE DISCLOSURE This invention relates to novel compounds andpharmaceutical compositions containing said compounds of the formula:

II ll a Ia.

wherein M is selected from the group consisting of hydrogen, aluminum,ammonium, sodium, potassium, calcium, andtris-(hydroxymethyl)methylammonium, R is selected from the groupconsisting of lower alkyl of 1 through 6 carbon atoms,

wherein X is selected from the group consisting of hydrogen, fluorine,chlorine, bromine, methoxy, methyl and trifluoromethyl, R is selectedfrom the group consisting of hydrogen and lower alkyl of 1 through 6carbon atoms, and R has the same meaning as R, and in addition hydrogen.

The compounds (12.) above are formulated with pharmaceutical carriersfor inhalation or for oral, parenteral or rectal administration, withinsufilation being the preferred method. The compositions are useful inthe prophylactic treatment of sensitized humans and mammals for allergicand all anaphylactic reactions of a reagin-mediated andnon-reagin-mediated nature.

CROSS REFERENCE TO RELATED APPLICATIONS None.

BRIEF SUMMARY OF THE INVENTION This invention relates to novel compoundsand pharmaceutical compositions of said compounds and a process for theprophylactic treatment of allergic conditions employing saidcompositions.

The novel compositions comprise a novel compound of the formula R1 T .l

a Ia

wherein X is selected from the group consisting of hydrogen, fluorine,chlorine, bromine, methoxy, methyl and trifluorornethyl, R is selectedfrom the group consisting United States Patent 6 of hydrogen and loweralkyl of 1 through 6 carbon atoms,

Patented Sept. 17, 1974 n CC and R, has the same meaning as R and inaddition, hydrogen, in association with a pharmaceutical carrier.

As employed in this application, the term lower alky includes methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tert, butyl, pentyl,isopentyl, neopentyl, hexyl, isohexyl and 3,3-dimethylbutyl.

The novel compounds (la) of this invention wherein R is hydrogen, and aprocess for their preparation are represented by the following sequenceof formulae:

acid R1 ON l t R N-C-C-OH \N H M wherein R is lower alkyl of 1 through 6carbon atoms, R R and M have the same meaning as above, R is hydrogenand X is selected from the group consisting of fluorine, chlorine, andbromine.

The compounds of Formula I are prepared by the acylation of thecorresponding Z-amino compounds of Formula H. The thus produced acylates(I) are converted to their corresponding metal salts (Ia) by mixing witha base; said salts yield corresponding hydroxy compounds (Ia) onacidification with an aqueous solution of a strong mineral acid.Alternatively, the hydroxy compounds (Ia) can be prepared by heating thecorresponding 2-amino compounds (II) with oxalic acid. A number ofcompounds of Formula II are known in the art, e.g., those prepared inthe manner described by Gewald in Z. Chem. 1, 349; numerous others (II)can be prepared by the condensation of a corresponding aminoketone ofFormula III (many of which are known in the art) by reaction withmalononitrile, followed by N -deacylation. The compounds of Formula IIIare prepared by the concomitant reduction and acylation of a known3-oxime of Formula 'IV.

The compounds embraced by Formula Ia of the flowsheet, above, whenemploying the compounds of Formula IV thereof as starting materials, areprepared by the procedures indicated therein, using the methods andreactions described below.

(1) The first step (IV- III) of the aforesaid flowsheet comprises theconcomitant reduction and acylation of a 3-oxime (IV), e.g., by itsreaction with hydrogen (in the presence of a catalyst such as palladiumon charcoal) and an anhydride of a hydrocarbon carboxylic acid (such asacetic anhydride, propionic anhydride, butyric anhydride and the like)in an acid medium (e.g., acetic acid,

propionic acid, butyric acid etc.), to yield a corresponding aminoketone (III), i.e., an N-(l-alkylhydrocarbonyl) acylamide (III).

(2) The next step (III- 11) involves the condensation of an amino ketone(III) produced in step (1) with malononitrile followed by N -deacylationto give a corresponding 2-amino-3-cyano-4-substituted (or4,5-disubstituted) pyrrole (II). The pyrrole (II) can be prepared, forexample, by (a) refluxing approximately equimolar amounts of an aminoketone (III) and malononitrile in ethanol or water with 1 equivalent ofsodium hydroxide or triethylamine and the corresponding pyrrole (II)crystallized by the addition of water or extraction with ether; or (b)mixing approximately equimolar amounts of III and the nitrile in thecold and adding 50% aqueous potassium hydroxide solution until a pH of12 to 13 is reached and a precipitate forms, which on warming dissolvesand following cooling and dilution with ice water gives thecorresponding pyrrole (II).

Alternatively, compounds of Formula II can be prepared by treatment ofamino ketones of the Formula V, prepared by reduction of compounds ofFormula IV in the absence of acyl anhydrides, in the usual manner withmalononitrile.

(3) The third step (II- I) of the process comprises the acylation of2-amino-3-cyano-4-substituted (or 4,5-disobstituted)pyrrole ('11)obtained in step (2), e.g., by slowly adding to a cold C.) solution of apyrrole (II) in a solvent such as ethyl acetate along with a base suchas triethylamine, an alkyl oxalyl halide (e.g., methyl oxalyl chloride,ethyl oxalyl chloride, butyl oxalyl fluoride, pentyl oxalyl bromide,etc.) [employing approximately equimolar amounts of pyrrole (H) andalkyl oxalyl halide], to yield a corresponding alkyl [3-cyano 4substituted (or 4,5-disubstituted)-2-pyrryl]oxamate (I).

(4) The fourth step (I-rIa) comprises mixing an oxamate (I) produced instep (3) with an aqueous solution of a base (e.g., ammonium hydroxide,sodium hydroxide, potassium or calcium hydroxide) at moderate (room)temperature, to give a corresponding [3 cyano-4-substituted (or4,5-disubstituted)-2-pyrryl]oxamic acid, metal salt (Ia).

(5) As a final step (I Ia) a metal salt of an oxamic acid (Ia) producedin step (4), on acidification (e.g., with a strong acid such as 1Naqueous hydrochloric acid, sulfuric acid or nitric acid) precipitates acorresponding [3- cyano-4-substituted (or 4,5 disubstituted) 2 pyrryl]oxamic acid (Ia).

Instead of employing the procedure of step (5), a 2-amino-3-cyano-4-substituted (or 4,5 disubstituted)pyrrole (II) onaddition thereto of an excess of oxalic acid (e.g., about 1 mole (II): 5moles oxalic acid), followed by heating (e.g., at about 200 C. for about2 hours), then cooling and diluting the mixture with ice-water, gives acorresponding [3-cyano-4-substituted (or 4,5 disubstituted) -2-pyrryl]oxamic acid (Ia).

The novel compounds (Ia) of this invention wherein R is other thanhydrogen, and a process for their preparation are represented by thefollowing sequence of formulae:

wherein R R M and X have the same meaning as is previously set forthfollowing the first sequence of formulae, whereas in the sequenceimmediately above, R is selected from the group consisting of loweralkyl of 1 through 6 carbon atoms and wherein X is selected from thegroup consisting of hydrogen, fluorine, chlorine, rnethoxy, methyl andtrifluoromethyl.

N -substituted compounds embraced by Formula Ia of the flow-sheet,immediately above, when employing the compounds of Formulae IVa plus IVbas starting materials, are prepared by the procedures indicated therein,using the methods and reactions described below.

(1) The first step (IVa+IVb III) of the aforesaid flow-sheet comprisesheating a mixture of a 3-hydroxy-2- alkanone (IVa) and a substituted orunsubstituted phenyl (or alkyl) amine (IVb) with formic acid to yield acorresponding w-substituted or unsubstituted phenyl (oralkyl)-2-alkanone ('III).

(2), (3), (4) and (5). Although the first step of this process isdifferent from the one for preparing the N unsubstituted compounds ofFormula Ia, the remaining steps, (2) through (5), are the same. Thus,subjecting a w-substituted or unsubstituted phenyl (or alkyl) 2 alkanone(III) produced in step (I) to these common procedures, yields acorresponding [3-cyano-4-substituted (or4,5-disubstituted)-1-substituted or unsubstituted phenyl (or alkyl)pyrrol-2-yl1oxamic acid (Ia) or a metal salt (Ia) thereof.

All of the compounds included within Formula Ia and the intermediates I,II and III therefor of the flow-sheet, above, can be isolated from theirrespective reaction mix tures by conventional means, for example, when awatermiscible solvent is used, by pouring the reaction mixture intowater and separating the resulting precipitate by filtration or byextraction with water-immiscible solvents. Additional purification ofthe products can be accomplished by conventional means, for example, byelution chromatography from an adsorbent column with a suitable solventsuch as acetone, ethyl acetate, ether, methylene chloride andSkellysolve B (hexanes), mixtures and combinations of these solvents;also by gradient elution chromatography from an adsorbent column with asuitable mixture of solvents, such as methylene chloride- Skellysolve B,acetone-Skellysolve B, and the like.

The novel compounds (I) of this invention have antiallergenic(especially anti-asthmatic) activity, inhibiting a positive PassiveCutaneous Anaphylactic (PCA) test induced by the rat immunochemicalcounterpart of human lgE (reagin), considered indicative of allergicactivity. This activity is apparent when these compounds are tested fortheir inhibition of the rats PCA reaction. The PCA assay is described byI. Mota in Ann. NY. Acad. Sci. 103, 264 (1963).

DETAILED DESCRIPTION The following preparations and examples areillustrative of the manner of making and using the invention and setforth the best mode contemplated by the inventor of carrying out hisinvention, but are not to be construed as limiting the scope thereof.

Preparation 1.2-amino-3-cyano-4,S-dimethylpyrrole (II) In a 500 ml.pressure bottle there is placed 10.11 g. (0.1 mole) of 2,3-butanedione3-monoxime (IV), prepared as in Org. Synthesis, Coll. Vol. 11, 204(1943), 1.5 g. of 5% palladium on carbon, 80 ml. of acetic acid and 20ml. of acetic anhydride. The bottle is put on a shaker hydrogenatingapparatus and hydrogen at 60 pounds per square inch admitted. Afterabout 40 minutes, the reaction is complete and the catalyst is removedby filtration. Three such reductions are carried out and the filtratescombined and concentrated under vacuum. The thus produced residual oil,N-(1-methylacetonyl)acetamide (III), is washed into a flask with about100 ml. of methanol and the flask placed in an ice-bath. To the chilledmixture 26.4 g. (0.4 mole) of malononitrile (or dicyanomethane) is addedwith stirring. To the stirring mixture, 50% aqueous potassium hydroxidesolution is added dropwise until a pH of 12 to 13 is reached. Shortlyafter this pH is obtained, a precipitate appears. The mixture containingthe precipitate is stirred for about minutes more at the coldtemperature, and then placed in a water bath at about 45 to 50 C. forabout 45 minutes. The precipitate dissolves to yield a red solution.This solution is cooled and diluted with about 400 to 500 ml. of icewater to give a precipitate which is collected and washed with coldwater until the filtrate is free of color. The precipitated crudepyrrole (II) amounting to about g. (about 50% of the theoretical yield)is recrystallized from aqueous methanol to yield 2-amino-3-cyano-4,S-dimethylpyrrole (II) melting at 165 to 168 C.

Preparation 2.2-amino-3-cyano-4,S-diethylpyrrole (II) Following theprocedure of Preparation 1 but substituting 3,4-hexanedione 4-oxime (IV)(prepared as in US. Patent 2,393,532) as starting material, yields 2-amino-3-cyano-4,5-diethylpyrrole (II).

Preparation 3.2-amino-3-cyano-4,S-dipropylpyrrole (II) Following theprocedure of Preparation 1 but substituting 4,5-octanedione 5-oxime (IV)(prepared as in Bull. Soc. Chim. 41, 1370) as starting material, yields2- amino-3-cyano-4,S-dipropylpyrrole (II).

Preparation 4.2-amino-3-cyano-4,5- diisopropylpyrrole (II) Following theprocedure of Preparation 1 but substituting 2,5-dimethyl-3,4-hexanedione4-oxime (IV) (prepared as in Ber. 16, 2991) as starting material, yields2-amino-3-cyano-4,S-diisopropylpyrrole (II).

Preparation 5.2amino-3cyano-4,5-dibutylpyrrole (II) Following theprocedure of Preparation 1 but substituting 5,6-decanedione 6-oxime (IV)(prepared as in J. Org. Chem. 24, 1726) as starting material, yields 2-amino-3-cyano-4,S-dibutylpyrrole (II).

Preparation 6.2-amino-3-cyano-4,5-dipenty1pyrrole (II) Following theprocedure of Preparation 1 but substituting 6,7-dodecanedi0ne 7-0xime(IV) (prepared as in Gazz. Chim. ital. 31, i, 406) as starting material,yields 2-amino-3-cyano-4,S-dipentylpyrrole (II).

Preparation 7.2-amino-3-cyano-4,5-dihexylpyrrole (II) Following theprocedure of Preparation 1 but substituting 7,8-tetradodecanedione8-oxime as starting material, yields 2-amino-3-cyano-4,5-hexylpyrrole(II).

Preparation 8.-2-amino-3-cyano-4-phenylpyrrole (II) To a solution of16.6 g. (0.097 mole) of 2-arninoacetophenone hydrochloride (V) (preparedas in J. Amer. Chem. Soc. 82, 459) in 50 ml. of absolute ethanol, 7.65g. (0.116 mole) of malononitrile and 9.85 g. (0.097 mole) oftriethylamine is added. The mixture is stirred for about 1 hour at roomtemperature and then poured into about 1 l. of water. The resultingprecipitate is removed by filtration, recrystallized from aqueousethanol and the solid that forms triturated with benzene to give 7.4 g.of 2-amino-3-cyano-4-phenylpyrrole (II) melting at to 172 C. Anadditional 2.6 g. of product (II) melting at 172 to 174 C. is obtainedfrom the mother liquors.

Preparation 9.2-amino-3-cyano-4- (p-bromo phenylpyrrole (11) Followingthe procedure of Preparation 8 but substituting2-arnino-4'-bromoacetophenone hydrochloride (V) (prepared as in Compt.rend. 230, 622) as starting material, yields 2-amino-3-cyano4-(p-bromo)phenylpyrrole (II).

Preparation 10.2-amino-3-cyano-4-(p-chloro)- phenylpyrrole (11)Following the procedure of Preparation 8 but substituting2-amino-4'-chloroacetophenone hydrochloride (V) (prepared as in Compt.rend. 230, 622) as starting mate rial, yields 2 amino 3cyano-(p-chloro)phenylpyrrole (II).

Preparation 1 1.-2-amino-3-cyano-4-(p-fluoro)- phenylpyrrole (II)Following the procedure of Preparation 8 but substituting2-amino-4-fiuoroacetophenone hydrochloride (V) (prepared as in J. Chem.Soc. 1950, 2776) as starting material, yields 2 amino 3cyano-4-(p-fiuoro)phenylpyrrole (II).

Preparation 12.2-amino-3-cyano-4- (m-bromo phenylpyrrole (II) Followingthe procedure of Preparation 8 but substituting2-amino-3-brornoacetophenone hydrochloride (V) (prepared as in Compt.rend. 230, 662) as starting mate rial, yields 2amino-3-cyano-4-(m-bromo)phenylpyrrole (II).

Preparation 13.- 2-amino-3-cyano-4-(m-chloro)- phenylpyrrole (II)Following the procedure of Preparation 8 but substituting2-amino-3'-chloroacetophenone hydrochloride (V) (prepared as in Compt.rend. 230, 662) as starting material, yields 2amino-3-cyano-4-(m-chloro)phenylpyrrole Preparation14.2-amino-3-cyano-4- (m-fluoro)- phenylpyrrole (II) Preparation 15.Z-amino-3-cyano-.4-(o-bromo)phenylpryrole (II) Following the procedureof Preparation 8 but substituting 2-amino-2-bromoacetophenonehydrochloride (V) (prepared as in Compt. rend. 230, 662) as startingmaterial, yields 2-arnino-3-cyano-4- (o-bromo)phenylpyrrole Preparation16. 2-amino-3-cyano-4-(o-chloro)phenylpyrrole (II) Following theprocedure of Preparation 8 but substitut- -ing2-amino-2-chloroacetophenone hydrochloride (V) (prepared as in Compt.rend. 230, 662) as starting material), yields2-amino-3-cyano-4-(o-chloro)phenylpyrrole Preparation 17.2-amino-3-cyano-4-(o-fluoro)phenylpyrrole (II) Following the procedureof Preparation 8 but substituting 2-amino-2'-fiuoroacetophenonehydrochloride (V) (prepared as in J. Chem. Soc. 1950, 2766) as startingmaterial, yields 2-amino-3-cyano-4-(o-fluoro)phenylpyrrole (II).

Preparation 18. 2-amino-3-cyano-4-(o-methoxy)phenylpyrrole (II)Following the procedure of Preparation 8 but substituting2-amin0-2-methoxyacetophenone hydrochloride (V) (prepared as in Ber. 44,1452) as starting material, yields 2-amino-3 -cyano-4- (o-methoxy)phenylpyrrole (II) Preparation 19.2-amino-3-cyano-4-(m-methoxy)phenylpyrrole (II) Following the procedureof Preparation 8 but substituting 2-amino-3-methoxyacetophenonehydrochloride (V) (prepared as in Ber. 44, 1452) as starting material,yields 2-amino-3-cyano-4-(m-methoxy)phenylpyrrole (II).

Preparation 20.-2-amino-3-cyano-4- (p-methoxy) phenylpyrrole (11)Following the procedure of Preparation 8 but substituting2-amino-4'-methoxyacetophenone hydrochloride (V) (prepared as in Ber.44, 1452) as starting material yields Z-amino-3-cyano-4-(p-methoxy)phenylpyrrole (II) Preparation 21.2-amino-3-cyano-4-(o-methyl)phenylpyrrole (II) Preparation 22.2-amino-3-cyano-4- (m-methyl)phenylpyrrole (II) Following the procedureof Preparation 8 but substituting 2-amino-3'-methylacetophenonehydrochloride (V) (prepared as in J. Chem. Soc. 1951, 255) as startingmaterial, yields 2-amino-3-cyano-4-(m-methyl)phenylpyrrole (II).

Preparation 23. 2-amino-3-cyano-4-(p-methyl)phenylpyrrole (II) Followingthe procedure of Preparation 8 but substituting2-amino-4-methylacetophenone hydrochloride (V) (prepared as in J. Chem.Soc. 1951, 255) as starting material, yields2-amino-3-cyano-4-(p-methyl)phenylpyrrole (II).

Preparation 24.2-arnino-3-cyano-5-methyl-4-phenylpyrrole (II) (a) To asolution of 13.05 g. (0.08 mole) of l-phenyl- 1,2-propanedione 2-oxime(IV) (prepared as in Atti. reale ist veneto sci 10, part 2, 261) in ml.of methanol and 7.78 ml. of concentrated hydrochloric acid, 200 mg. ofplatinum oxide catalyst is added. The resulting mixture is hydrogenatedat an initial pressure of 3 atmospheres. When the uptake of hydrogen iscomplete, the catalyst is removed by filtration and the filtrateevaporated to dryness. The residue is first triturated with ether, thenacetone, and recrystallized from ethanol-ether to giveZ-aminopropiophenone hydrochloride (V).

(b) To a solution of 6.1 g. (0.033 mole) of Z-aminopropiophenonehydrochloride (V) [prepared as in (a), above] in 60 ml. of ethanol, 2 g.(0.0396 mole) of malononitrile is added. To the resulting solution, 3.35g. (0.033 mole) of triethylamine is added with stirring at roomtemperature, which is continued for about 1 hour. This mixture is pouredinto 350 ml. of Water to give a yellow precipitate that is removed byfiltration and washed with water to yield 4.32 g. (65% yield) of2amino-3- cyano-S-methyl-4-phenylpyrrole (II), melting at 184 to 186 C.

Preparation 25 .--2-amino-3 -cyano-5-methyl-4- p-chloro) phenylpyrrole(II) Following. the procedure of Preparation 24 (b) but substituting2-amino-4-chloropropiophenone hydrochloride (V) (prepared as in Ann.599, 61) as starting ma terial yieldsZ-amino-3-cyano-5-methyl-4-(p-chloro)phenylpyrrole (II).

Preparation 26. 2-amin0-3-cyano-5-methyl-4-(p-fluoro) phenylpyrrole (II)Following the procedure of Preparation 24 (b) but substituting2-amino-4'-fiuoropropiophenone hydrochloride (V) (prepared as in Ann.599, 61) as starting material, yieldsZ-amino-3-cyano-5-methyl-4-(p-fiuoro)phen ylpyrrole (II).

Preparation 27.2-amino-3-cyano-5-methyl-4- (p-bromo) phenylpyrrole (II)Following the procedure of Preparation 24 (b) but substituting2-amino-4'-bromopropiophenone hydrochloride (V) (prepared as in Ann.599, 61) as starting material, yields2-amino-3-cyano-5-methyl-4-(p-bromo)phenylpyrrole (II).

Preparation 28.2-amino-3-cyano-5-methyl-4-(mchloro) -phenylpyrrole (II)Following the procedure of Preparation 24 (b) but substituting2-amino-3'-chloropropiophenone hydrochloride (V) (prepared as in Ann.599, 61) as starting material, yields 2 amino 3cyano-5-methyl-4-(m-chloro) phenylpyrrole (II).

Preparation 29 .2-amino-3-cyano-5-methyl-4-(o-fiuoro phenylpyrrole (II)Following the procedure of Preparation 24 (b) but substituting2-amino-2'-fiuoropropiophenone hydrochloride (V) (prepared as in Ann.599, 61) as starting material, yields2-amino-3-cyano-S-methyl-4-(o-fiuoro)phenylpyrrole (II).

Preparation 30.2-amino-3-cyano-5-methyl-4-(rnmethoxy) -phenylpyrrole(II) Following the procedure of Preparation 24 (b) but substituting2-amino-3'-methoxypropiophenone hydrochloride (V) (prepared as in S.African Patent 67 07, 302) as starting material, yieldsZ-amino-3-cyano-5-methyl-4- (m-methoxy)phenylpyrrole (II).

9 Preparation 31.--2-amino-3-cyano-5-methyl- 4-(p-methoxy)-phenylpyrrole(II) Following the procedure of Preparation 24(b) but substituting3-amino-4'-methoxypropiophenone hydrochloride (V) (prepared as in S.African Patent 67 07, 302) as starting material, yields2-amino-3-cyano-4-(p-methoxy) phenylpyrrole (II).

Preparation 32.-2-amino-3-cyano-5-methyl- 4-(p-ethyl)phenylpyrrole (I'I)Preparation 33.--2-amino-3-cyano-5-methyl- 4- p-ethyl phenylpyrrole (II)Following the procedure of Preparation 24 (b) but substituting2-amino-4'-ethylpropiophenone hydrochloride (V) [prepared as in Pharm.Bull. (Japan) 4, 182] as starting material, yields2-amino-3-cyano-5-methyl-4- (p-ethyl phenylpyrrole (II) Preparation34.2-amino-3-cyano-5-methyl- 4- (m-methyl phenylpyrrole (11) Followingthe procedure of Preparation 24(b) but substituting2-amino-3'-methylpropiophenone hydrochloride (V) [prepared as in Bull.Pharm. (Japan) 4, 182] as starting material, yields2-amino-3-cyano-5methyl-4- (In-methyl) phenylpyrrole (II) Preparation35.-2-amino-3-cyano-5-methyl- 4-(o-methyl)phenylpyrrol (II) Followingthe procedure of Preparation 24(b) but substitutingZ-amino-2-methylpropiophenone hydrochloride (V) [prepared as in Bull.Pharm. (Japan) 4, 182] as starting material, yields 2-amino 3cyano-5-methyl-4- (o-methyl)phenylpyrrole (II).

Preparation 36.2-amino-3-cyano-4-methylpyrrole (H) Following theprocedure of Preparation 1 but substituting 1,2-propanedione l-oxime(also named isonitrosoacetone or pymvaldoxime, and prepared as in J.Chem. Soc. 117, 589) as starting material, yields 2-amino-3-cyano-4-methylpyrrole (II) Example 1.Ethy1 (3 cyano 4,5dimethyl-Z-pyrryl) oxamate [also namedethyl(3-cyano-4,5-dimethylpyrrol-2-yl)oxamate] (I) To 10 g. (0.074 mole)of 2-arnino-3-cyano-4,S-dimethylpyrrole (II) (obtained as inPreparation 1) dissolved in 300 ml. of ethyl acetate, 7.59 g. oftriethylamine is added. To this solution at about C., 10.24 g. of ethyloxalyl chloride in 25 ml. of ethyl acetate is added slowly withstirring. A yellow precipitate forms immediately, and the reactionmixture is stirred for about 2 hours in an ice-bath and for about 1 hourat room temperature. The triethylamine hydrochloride is removed byfiltration and the filtrate stored for about 16 hours. Evaporation ofthe solvent under vacuum gives a reddish solid having a melting point of110 to 120 C. Recrystallization from 95% ethanol yields 11.5 g. ofbright yellow ethyl (3-cyano- 4,5-dimethyl-2-pyrryl) oxamate (I), havinga melting point of 132 to 133 C.

Following the procedure of Example 1 but substituting another al-kyloxalyl halide for ethyl oxalyl chloride, such as (1) methyl oxalylchloride,

(2) propyl oxalyl chloride,

(3) isopropyl oxalyl chloride,

(4) butyl oxalyl chloride,

(5) isobutyl oxalyl chloride,

(6) pentyl oxalyl chloride,

(7) hexyl oxalyl fluoride, etc.,

yields respectively,

( 1) methyl (3-cyano 4,5 dimethyl-2-pyrryl)oxamate 2) propyl (3 cyano4,5 dimethyl-Z-pyrryl)oxamate 3) isopropyl (3-cyano 4,5dimethyl-2-pyrryl)oxamate (I),

(4) butyl (3-cyano 4,5 dimethyl-Z-pyrryl)oxamate 5) isobutyl (3-cyano4,5 dimethyl-2-pyrryl)oxamate (I),

(6) pentyl (3-cyano 4,5 dimethyl-Z-pyrryl)oxamate 7) hexyl (3-cyano 4,5dimethyl-2-pyrryl)oxamate (I), etc.

Following the procedure of Example 1 and the paragraph thereafter butemploying another pyrrole (II) as starting material and reacting it withthe same or another alkyl oxalyl halide, such as (1)2-amino-3-cyano-4,S-diethylpyrrole (II) (obtained as in Preparation 2)and methyl oxalyl chloride,

(2) Z-amino 3 cyano-4,5-dipropylpyrrole (II) (obtained as in Preparation3) and propyl oxalyl fluoride,

(3) 2 amino 3 cyano-4,S-diisopropylpyrrole (II) (obtained as inPreparation 4) and ethyl oxalyl chloride,

(4) 2-amino 3 cyano-4,5-dibutylpyrrole (II) (obtained as in Preparation5) and isopropyl oxalyl chloride,

(5) Z-amino 3 cyano-4,S-dipentylpyrrole (II) (obtained as in Preparation6) and butyl oxalyl fluoride,

(6) Z-amino 3 cyano-4,5-dihexylpyrrole (II) (obtained as in Preparation7) and hexyl oxalyl chloride,

(7) 2-amino 3 cyano-4-phenylpyrrole (II) (obtained as in Preparation 8)and ethyl oxalyl chloride,

(8) 2-amino 3 cyano-4-(p-bromo)phenylpyrrole (II) (obtained as inPreparation 9) and isobutyl oxalyl fluoride,

(9) 2-amino 3 cyano-4-(p-chloro)phenylpyrrole (II) (obtained as inPreparation 10) and methyl oxalyl chloride,

(10) 2-amino-3-cyano-4-(p-fluoro)phenylpyrrole (II) (obtained as inPreparation 11) and ethyl oxalyl chloride,

(11) 2-amino 3 cyano-4-(m-brorno)phenylpyrrole (II) (obtained as inPreparation 12) and propyl oxalyl chloride,

(12) Z-amino 3 cyano-4-(m-chloro)phenylpyrrole (II) (obtained as inPreparation 13) and hexyl oxalyl chloride,

(13) 2-amino 3 cyano-4-(m-fluoro)phenylpyrrole (II) (obtained as inPreparation 14) and butyl oxalyl chloride,

(14) 2-amino 3 cyano-4-(o-bromo)phenylpyrrole (II) (obtained as inPreparation 15) and ethyl oxalyl chloride,

(15) 2-amino 3 cyano-4-(o-chloro)phenylpyrrole (II) (obtained as inPreparation 16) and methyl oxalyl chloride.

(16) 2-amino 3 cyano-4-(o-fiuoro)phenylpyrrole (II) (obtained as inPreparation 17) and ethyl oxalyl fluoride,

(17) 2-amino 3 cyano-4-(o-methoxy)phenylpyrrole (H) (obtained as inPreparation 18) and propyl oxalyl chloride,

(18) 2-amino 3 cyano-4-(m-methoxy)phenylpyrrole (II) (obtained as inPreparation 19) and pentyl oxalyl fluoride,

(19) 2-amino 3 cyano-4-(p-methoxy)phenylpyrrole (II) (obtained as inPreparation 20) and hexyl oxalyl chloride,

(20) Z-amino 3- cyano-4-(o-methyl)phenylpyrrole (II) (obtained as inPreparation 21) and butyl oxalyl fluoride,

(21) Z-amino 3 cyano-4-(m-methyl)phenylpyrrole (II) (obtained as inPreparation 22) and methyl oxalyl fluoride,

(22) Z-amino 3 cyano-4- (p-methyl)phenylpyrrole (II) (obtained as inPreparation 23) and ethyl oxalyl chloride,

(23) Z-amino 3-cyano-5-methyl-4-phenylpyrrole (11) (obtained as inPreparation 24) and ethyl oxalyl chloride,

(24) Z-arnino 3 cyano--methyl-4- (p-chloro)phenylpyrrole (11) (obtainedas in Preparation 25) and methyl oxalyl chloride,

(25) 2-amino 3 cyano-5-methyl-4(p-fiuoro)phenylpyrrole (II) (obtained asin Preparation 26) and ethyl oxalyl chloride,

(26) Z-amino 3 cyano-5-methyl-4-(p-bromo)phenyl pyrrole (II) (obtainedas in Preparation 27) and methyl oxalyl chloride,

(27) Z-amino 3 cyano-5-methyl-4-(m-chloro)phenylpyrrole (II) (obtainedas in Preparation 28) and methyl oxalyl fluoride,

'(28) Z-amino 3 cyano-5-methyl-4-(o fiuoro)phenylpyrrole (II) (obtainedas in Preparation 29) and ethyl oxalyl chloride,

(29) 2-arnino 3 cyano 5-methyl-4-(mmethoxy) phenylpyrrole (II) (obtainedas in Preparation 30) and ethyl oxalyl chloride,

(30) 2-amir1o 3 cyano-5-methyl-4- (p-methoxy)phenylpyrrole (II)(obtained as in Preparation 31) and butyl oxalyl chloride,

(31) 2-amino 3 cyano-5-methyl-4-(p-methyl)phenylpyrrole (II) (obtainedas in Preparation 32) and ethyl oxalyl chloride,

(32) 2-amino 3 cyano-S-methyl-4-(p-ethyl)phenylpyrrole (II) (obtained asin Preparation 33) and methyl oxalyl chloride,

(33) 2-amino 3 cyano-5-methyl-4-(m-methyl)phenylpyrrole (II) (obtainedas in Preparation 34) and ethyl oxalyl chloride,

(34) Z-amino 3 cyano-5-methyl-4- (o-methyl)phenylpyrrole (11) (obtainedas in Preparation 35) and ethyl oxalyl chloride,

(35) Z-amino 3 cy-ano-4-methylpyrro1e (II) (obtained as in Preparation36) and ethyl oxalyl chloride, etc., yields respectively,

( 1) methyl (3-cyano-4,S-diethyl-Z-pyrryl)oxamate (I), (2) propyl(3-cyano 4,5 dipropyl-Z-pyrryl)oxamate (3) ethyl (3-cyano 4,5diisopropyl-Z-pyrryl)oxamate (4) isopropyl (3-cyano 4,5dibutyI-2-pyrryl)oxamate (5) butyl (3-cyano 4,5dipentyl-Z-pyrryl)oxamate (6) hexyl(3-cyano-4,S-diheXyI-Z-pyrryl)oxamate (I),

(7) ethyl (3-cyano phenylpyrrole2-yl)oxamate (I),

(8) isobutyl [3-cyano 4 (p-brorno)phenylpyrr0le- 2-yl]oxamate (I),

(9) methyl [3-cyano 4 (p-chloro)pheny1pyrrol-2- ylEoxamate (I),

(10) ethyl [3-cyano 4 (p-fluoro)phenylpyrrol-Z-yl] oxamate (I) (11)propyl [3-cyano 4 (m-bromo)phenylpyrrol-2- ylfoxam ate (I),

(12) hexyl [3-cyano 4 (m-chloro)phenylpyrrol-Z- ylIoxamate (I),

(13) butyl [3-cyano 4 (m-fluoro)phenylpyrrol-Z-yl] oxamate (I),

(14) ethyl [S-cyano 4 (o-bromo)phenylpyrrol-Lyl] oxamate (I),

(15) methyl [3-cyano 4 (o-chloro)phenylpyrrol-2 yl[oxamate (I),

(16) ethyl [3-cyano 4 (o-fluoro)phenylpyrrol-Z-yl] oxamate (I),

(17) propyl [3-cyano 4 (o-rnethoxy)phenylpyrrol- 2-yl]oxamate (I),

(18) pentyl [3-cyano 4 (m-methoxy)phenylpyrro1- 2-yl1oxamate (I),

(19) hexyl [3-cyano 5 (p-methoxy)phenylpyrrol-2- yl[oxam ate (I),

(20) butyl [3-cyano 4 (o-methyl)phenylpyrrol-Z-yl] oxamate (I),

(21) methyl [3-cyan0 4 (m-methyl)phenylpyrrol-Z- ylioxamate (I),

22) ethyl [3-cyano 4 (p-methyl)phenylpyrrol-Z-yl] oxamate (I),

(23) ethyl [3-cyano 5 methyl-4-phenylpyrrol-2-yl] oxamate (I),

(24) methyl [3-cyano 5 methyl-4-(p-chloro)phenylpyrrol-Z-yllox-amate*(I) (25) ethyl [3-cyano 5 methyl-4-(p-fiuoro)phenylpyrrol-2-yl1oxamate'(I),

(26) methyl [3-cyano 5 methyl-4-(p-bromo)phenylpyrrol-Z-yl] oxamate '(I(27) methyl [3-cyano 5 methyl-4-(m-ch1oro)pheny1- pyrrol-2-yl1oxamate(I),

(28) ethyl [3-cyano 5 methyl-#(o-fluoro)phenylpyrrol-2-yl1oxamate (I),

(29) ethyl [3-cyano 5 methyl-4-(m-methoxy)phenylpyrrol-2-yl] oxamate (I)(30) butyl [3-cyano 5 methyl-4-(p-methoxy)pheny1- pyrrol-2-yl1ox-amate(I),

(31) ethyl [3-cyano 5 methyl-4-(p-methyl)phenylpyrrol-Z-yljoxamate (I),

(32) methyl [3-cyano 5 methyl-4-(p-ethyl)phenylpyrrol-Z-ylloxamate '(I),

(33) ethyl [3-cyano 5 methyl-4-(m-methyl)phenylpyrrol-2-yl1oxamate (I),

(34) ethyl [3-cyano 5 methyl-4-(o-methyl)phenylpyrrol-Z-yl ox'am ate (1(35) ethyl (Z-cyano 4 methyl-2-pyrryl)oxamate (I), etc.

Example 2 (3-cyano-4,S-dimethylpyrrol-Z-yl)oxamic acid, sodium salt (Ia)A mixture of ethyl (3-cyano-4,5-dimethyl-2-pyrrol-2-yl) oxamate (I)(obtained as in Example 1) and and 20 of 5% sodium hydroxide solution isstirred at room temperature for about 20 minutes and then filtered, thefunnel being rinsed with two 5 ml. portions of 5% sodium hy droxidesolution. The combined filtrate is neutralized by the addition of aceticacid. The precipitate that forms is removed by filtration andrecrystallized from 50% ethanol-water to yield 1.54 g. of light tanneedles of (3-cyano- 4,S-dimethylpyrrol-Z-yl)oxamic acid, sodium salt(Ia) melting at 245 C. (with decomposition).

Anal.Calcd. for C H N O Na: C, 47.16; H, 3.52; N, 18.33; Na, 10.04.Found: C, 46.52; H, 3.62; N, 18.24; Na, 10.0 8.

Following the procedure of Example 2 but substituting another compoundof Formula I as starting material, such as 1) methyl(3-cyano-4,5-diethyl-Z-pyrryl)oxamate (I),

(2) propyl (3cyano-4,5-dipropyl-2-pyrryl oxamate (I),

(3) ethyl (3-cyano-4,S-diisopropyl-Z-pyrryl)oxamate (5) butyl(3-cyano-4,S-dipentyl-Z-pyrryl)oxamate (I),

(6) hexyl (3-cyano-4,5-dihexyl-2-pyrryl)oxamate (I),

(7) ethyl (3-cyano-4-phenylpyrrol-2-yl)oxamate (I),

(8) isobutyl [3-cyano-4(p-bromo)phenylpyrrol-Z-yl] oxamate (I),

(9) methyl [3-cyano-4- (p-chloro phenylpyrrol-2-yl1- oxamate (I),

(10) ethyl [3-cyano-4-(p-fluoro)phenylpyrrol-2 yl]- oxamate (I),

11 propyl [3-cyano-4-(m-bromo)phenylpyrrol-2-yl]- oxamate (I),

12) hexyl [3-cyano-4-(m-chloro)phenylpyrrol-2-yl1- oxamate (I),

(13) butyl [3-cyano-4-(m-fluoro)phenylpyrrol-2-y11- oxamate (I),

isopropyl (3-cyano-4,5-dibutyl-2-pyrryl) oxamate l4) ethyl[3-cyano-4-(o-bromo)phenylpyrrol-2-yl1- oxamate (I),

(15) methyl [3-cyano-4-(o-chloro)phenylpyrrol-Z-yl]- oxamate (I),

(16) ethyl [3-cyano-4-(o-fiuoro)phenylpyrrol-2 yl]- oxamate (I),

(17) propyl [3-cyano-4-(o-methoxy)phenylpyrrol 2- yl]-oxamate (I),

(18) pentyl [3-cyano-4-(m-methoxy)phenylpyrrol 2- yl]-oxamate (I),

(19) hexyl [3-cyano-4-(p-methoxy)phenylpyrrol-Z-yl]- oxamate (I),

(20) butyl [3-cyano-4-(o-methyl)phenylpyrrol-Z-yl]- oxamate (I),

(21) methyl [3-cyano-4-(m-methyl)phenylpyrrol 2- yll-oxamate (I),

(22) ethyl [3-cyan0-4-(p-methyl)phenylpyrrol-Z-yl]- oxamate (I),

(23) ethyl [3-cyano-5-methyl-4-phenylpyrrol-2 yl]- oxamate (I),

(24) methyl [3-cyano-5-methyl-4(p-chloro)phenylpyrrole-2-yl1oxamate (I),

(25) ethyl [3-cyano-5-methyl-4-(p-chloro)phenylpyrrol-2-yl1oxamate (I),

(26) methyl [3-cyar1o-5-methyl-4- (p-bromo)phenylpyrrol-2-yl]oxamate(I),

(27) methyl [3-cyan0-5-methyl-4-(m-chloro)phenylpyrrol-Z-yl] oxamate (I)(28) ethyl [3-cyano-5-methyl-4-(o-fluoro)phenylpyrrol-2-yl] oxamate (I),

(29) ethyl [3-cyan0-5-methyl-4-(m-methoxy)phenylpyrrol-2-yl1oxamate (I)(30) butyl [3-cyano-5-methyl-4-(p-methoxy)pheny1- pyrrol-2-yl] oxamate(I) (31) methyl [3-cyano-5-methyl-4-(p-methyl)phenylpyrrol-Z-yl] oxamate(I),

(32) methyl [3-cyano-5-methyl-4-(p-ethyl)phenylpyrrol-2-yl]oXamate (I),

(33) ethyl [3-cyano-5-methyl-4-(p-methyl)phenylpyrrol-2-yl]oxamate (I),

(34) ethyl [3-cyano-5-methyl-4-(o-methyl)phenylpyrrol-2-y1]oxamate (I),

(35) ethyl (3-cyano-4-methyl-2-pyrryl)oxamate (I), etc., yields,respectively,

(1) (3-cyano-4,5 diethyl-2-pyrryl) oxamic acid, sodium salt (Ia).

(2) (3-cyano-4,5-dipropyl-2-pyrryl)oxamic acid, sodium salt (la),

(3) (3-cyano-4,S-diisopropyl-Z-pyrryl)oxamic acid, sodium salt (la),

(4) (3-cyano-4,5-dibutyl-2-pyrryl)oxamic acid, sodium salt (Ia),

(5) (3-cyano-4,5-dipentyl-2-pyrryl)oxamic acid, sodium salt (la),

(6) (3-cyano-4,5-dihexyl-2-pyrryl)oxamic acid, sodium salt (la),

(7) (3-cyano-4-phenylpyrrol-2-yl)oxamic acid, sodium salt (Ia),

(8) [3-cyano-4-(p-bromo)phenylpyrrol-2 yl]oxamic acid, sodium salt (Ia),

(9) [3-cya11o-4-(p-chloro)phenylpyrrol-2 yl]oxamic acid, sodium salt(Ia),

(10) [3-cyano-4-(p-fluoro)phenylpyrrol-2 yl]oxamic acid, sodium salt(Ia),

11) [3-cyano-4-(m-bromo) phenylpyrrol-2-yl1oxamic acid, sodium salt(la),

(12) [3-cyano-4-(m-chloro)phenylpyrrol-2-yl1oxamic acid, sodium salt(Ia),

(13) [3-cyano-4(m-fluoro)phenylpyrrol-2 yl] oxamic acid sodium salt(la),

(14) [3-cyano-4- (o-bromo)phenylpyrrol-2 yl]oxamic acid, sodium salt(Ia),

(15 [3cyano-4-(o-chloro)phenylpyrro1-2 yl]oxamic acid, sodium salt (Ia),

(16) [3-cyano-4-(o-fiuoro)phenylpyrrol-2 yl]oxamic acid, sodium salt(Ia),

(l7) [3-cyano-4-(o-methoxy)phenylpyrrol-2 yl]oxamic acid, sodium salt(la),

(18) [3-cyano-4-(m-methoxy)phenylpyrrol-Z yl] 0xamic acid, sodium salt(Ia),

(l9) [3-cyano4-(p-methoxy)phenylpyrrol-2 yl]oxamic acid, sodium salt(la),

(20) [3 cyano 4 (o-methyl)phenylpyrrol-2-yl] oxamic acid, sodium salt(Ia),

(21) [3 cyano 4 (m-methyl)phenylpyrrol-Z-yl] oxamic acid, sodium salt(Ia),

(22) [3 cyano 4 (p-methyl)phenylpyrrol-Z-yl] oxamic acid, sodium salt(la),

(23) [3 cyano 4 methyl 4-phenylpyrrol-2-yl] oxamic acid, sodium salt(Ia),

(24) [3 cyano 5 methyl-4-(p-chloro)phenylpyrrol- 2-yl] oxamic acid,sodium salt (Ia),

(25) [3 cyano 4-methyl-4-(p-chloro)phenylpyrrol- 2-yl]oxamic acid,sodium salt (Ia),

26) [3 cyano 5 methyl-4-(p-bromo)phenylpyrrol- 2-yl]oxamic acid, sodiumsalt (Ia),

27) [3 cyano 5 methyl-4- (m-chloro)phenylpyrrol- 2-yl]oxamic acid,sodium salt (Ia),

(28) [3 cyano 5-methyl-4-(o-fluoro)phenylpyrrol- 2-y11oxamic acid,sodium salt (Ia),

(29) [3 cyano-5-methyl-4-(m-methoxy)phenylpyrrol 2-yl]oxamic acid,sodium salt (Ia),

30) [3 cyano-5-methyl-4-(p-methoxy)phenylpyrrol- 2-yl]oxamic acid,sodium salt (Ia),

(31) [3 cyano 5-methyl-4-(p-methyl)phenylpyrrol 2-yl]oxamic acid, sodiumsalt (Ia),

(32) [3 cyano 5-methyl-4- (p-ethyl) phenylpyrro1 2-yl]oxamic acid,sodium salt (Ia),

33) [3 cyano 5 -methyl-4-(p-methyl)phenylpyrrol- 2-yl]oxamic acid,sodium salt (Ia),

(34) [3 cyano 5-methyl-4-(o-methyl)phenylpyrrol- 2-yl1oxamic acid,sodium salt (Ia),

(35) (3 cyano 4 methyl-2-pyrryl)oxamic acid, sodium salt (Ia),

Following the procedure of the immediately preceding paragraph and ofExample 2, but substituting in the latter another hydroxide (e.g.,ammonium hydroxide, potassium hydroxide or calcium hydroxide) for sodiumhydroxide, yields a corresponding [3-cyano-4-substituted (or4,5-disubstituted)-2-pyrryl]oxamic acid, metal salt (Ia).

Example 3 (3-cyano-4,S-dimethylpyrrol-Z-yl)oxamic acid (Ia) A solutionof 0.5 gm. of (3-cyano-4,5-dimethylpyrrol-2- yl)oxamic acid, sodium salt(Ia) (prepared as in Example 2) in 50 ml. of water is filtered. Thefiltrate is acidified by the addition of aqueous 1N hydrochloric acid.The yellow precipitate that forms is filtered and washed with water togive 370 mg. of product (Ia) melting at 237 C. (with decomposition).Recrystallization from ethanol gives(3-cyano-4,S-dimethylpyrrol-Z-yl)oxamic acid (Ia) having a melting pointof 237 C. (with decomposition).

Analysis.Calcd. for C H N O C, 52.17; H, 4.38; N, 20.28. Found: C,51.71; H, 4.37; N, 19.74.

Following the procedure of Example 3 but substituting another[3-cyano-4-substituted (or 4,5-disubstituted)- pyrrol-2-yl1oxamic acid,metal salt (Ia) (obtained as in Example 2 and the paragraphs thereafter)such as (l) (3 cyano 4,5 dipropylpyrrol-Z-yl)oxamic acid, sodium salt(la),

(2) (3 cyano 4,5 dipentylpyrrol-Z-yl)oxamic acid, potassium salt (Ia),

(3) (3 cyano 4 phenylpyrrol-2-yl)oxamic acid, calcium salt (Ia),

(4) [3 cyano 4-(o-fiuoro)phenylpyrrol-Z-yl)oxamic acid, ammonium salt(Ia),

(5) [3 cyano-4-(m-chloro)phenylpyrrol-Z-yl]oxamic acid, sodium .salt(Ia),

(6) [3 cyano 4 (p-methoxy)phenylpyrrol-2-yl] oxarnic acid, ammonium salt(Ia),

(7) [3 cyano 4 (o-methyl)phenylpyrrol-Z-yl] oxamic acid, potassium salt(Ia),

8) (3 cyano methyl-4-phenylpyrrol-2-yl)oxamic acid, calcium salt (Ia),

(9) [3 cyano 5 methyl-4-(o-fluoro)phenylpyrrol-2- yl]oxamic acid,ammonium salt (Ia),

[3 cyano-5-methyl-4 (m-methoxy)phenylpyrrol- 2-yl]oxamic acid, sodiumsalt (Ia),

(11) [3 cyano 5-methyl-4-(p-methyl)phenylpyrrol- 2-yl]oxamic acid,potassium salt (Ia),

(12) (3 cyano 4-methylpyrrol-2-yl)oxamic acid, calcium salt (Ia), etc.yields, respectively,

(1) (3 cyano 4,5 dipropylpyrrol-Z-yl)oxamic acid 2) (3 cyano 4,5dipentylpyrrol-Z-yl)oxamic acid (3) (3 cyano 4 phenylpyrrol-Z-yDoxamicacid (4) [3 cyano 4-(o-fluoro)pheny1pyrro1-2-yl1oxamic acid (Ia),

(5) [3 cyano 4-(m-chloro)phenylpyrrol-2-yl1oxamic acid (Ia),

(6) [3 cyano 4 (p-methoxy)phenylpyrrol-Z-yl1 oxamic acid (Ia),

(7) [3 cyano 4-(o-methyl)phenylpyrrol-Z-yl]oxamic acid (Ia),

(8) [3 cyano 5' methyl-4-phenylpyrrol-2-y1] oxamic acid (Ia),

(9) [3 cyano 5 methyl 4 (o-fluoro)phenylpyrrol- 2-yl] oxamic acid (Ia),

(10) [3 cyano-5-methyl-4-(m-methoxy)phenylpyrrol- 2-y1] oxamic acid(Ia),

(11) [3 cyano S-methyl-4-(p-methyDphenylpyrrol- 2-yl]oxamic acid (Ia),

(12) (3 cyano 4-methylpyrrol-2-yl)oxamic acid (Ia), etc.

Example 4 (3-cyano-4,S-dimethylpyrrol-Z-yl) oxamic acid (Ia) To 12.1 g.(0.1 mole) of 2-aInino-3-cyano-4,5-dimethylpyrrole (II) (obtained as inPreparation 1) an excess of oxalic acid (0.5 mole) is added. Theresulting mixture is heated at about 200 C. for about 2 hours, cooled atroom temperature, and diluted with ice-Water; the resulting solid isremoved by filtration, Washed with Water, and recrystallized fromethanol, to give (3-cyano-4,5-di methylpyrrol-2-yl)oxamic acid (Ia),having a melting point of 237 C. (with decomposition).

Following the procedure of Example 4 but employing another pyrrole (II)as starting material, such as (17) Z-amino 3cyano-4-(o-methoxy)phenylpyrrole (18) Z-amino 3cyan0-4-(m-methoxy)phenylpyrrole (1 9) Z-amino 3 cyano-4-(p-methoxy)phenylpyrrole (20) 2-amino-3-cyano-4-(o-methyl)pheny1pyrrole (II),

(21) 2-amino-3-cyano-4- (m-methyl)phenylpyrrole (II),

(22) 2-arnino-3-cyano-4-(p-methyl)phenylpyrrole (II),

(23) Z-amino-3-cyano-S-methyli-phenylpyrrole (II),

(24) 2-amino-3-cyano-5-methyl-4- (p-chloro)phenylpyrrole 11 (25)Z-amino-3-cyano-5-methyl-4-(p-fluoro)phenylpyrrole (II),

(26) 2-amino-3-cyano-5-methyl-4- (p-bromo) phenylpyrrole (II),

(27) 2 amino-3-cyano-5-methyl-4-(m-chloro)phenylpyrrole (II),

(28) 2-amino 3 cyano-5-methyl-4- (o-fluoro)phenylpyrrole (II),

(29) 2 amino 3 cyano-5-me-thyl-4-(m-methoxy) phenylpyrrole (II),

(30) 2-amino-3-cya11o-5methyl-4-(p-methoxy)phenylpyrrole (II),

(31) 2 amino-3-cyano-5-methyl-4-(p-mcthyl)phenylpy (32) 2-amino 3cyano-5-methyl-4-(p-ethyl)pheny1 pyrrole (II),

(33) 2 amino-3-cyano-5-methyl-4-(m-methyl)phenylpyrrole (H),

(34) 2 amino-3-cyano-5-methyl-4-(o-methyDphenylpyrrole (II),

(35) Z-amino-3-cyano-4-methylpyrrole (II) etc yields respectively,

(1) (3-cyano-4,5-diethyl-2-pyrryl)oxamic acid (Ia),

(2) (3-cyano-4,5-dipropyl-2-pyrryl)oxamic acid (Ia),

(3) (3-cyano-4,5-diisopropyl 2 pyrryl)oxamic acid(3-cyano-4,S-dibutyl-Z-pyrryl)oxamic acid (Ia),(3-cyano-4,S-dipentyl-Z-pyrryl)oxamic acid (Ia),(3-cyano-4,S-diheXyl-Z-pyrryl)oxamic acid (Ia),

(7) (3-cyano-4-phenylpyrrol-2-yl)oxamic acid (Ia),

(8) [3 cyano-4-(p-bromo)phenylpyrrol-Z-yl]oxamic acid (Ia),

(9) [3 cyano- L(p-chloro)phenylpyrrol-Z-yl]oxamic acid (Ia),

-(10) [3-cyano-4-(p-fluoro)phenylpyrr0l-2 yl]oxamic acid (1a),

(11) [3 cyano-4-(m-bromo)phenylpyrrol-Z-yl] oxamic acid (Ia),

(12) [3 cyano-4-(m-chloro)phenylpyrrol-2-yl1oxamic acid (Ia),

(13) [3 cyano4-(m-fiuoro)phenylpyrrol-Z-yl}oxamic acid (Ia),

(14) [3 cyano-4-(o-bromo)phenylpyrrol-Z-yl] oxamic acid (Ia),

(15) [3 cyano-4-(o-chloro)phenylpyrrol-2-yl1oxamic acid (Ia),

(16) [3 cyano-4-(o-fluoro)phenylpyrrol-2-yl]oxamic acid (Ia),

(17) [3-cyano-4-(o-methoxy)phenylpyrrol-Z-yl]oxamic acid (Ia),

(18) [3-cyano 4 (m-methoxy)phenylpyrrol-Z-yl] oxamic acid (Ia),

(19) [3-cyano-4-(p-methoxy)phenylpyrrol-Z-yl]oxamic acid (Ia),

(20) [3 cyano-4-(o-methyl)phenylpyrrol-Z-ylJoxamic acid (Ia),

(21 [3-cyano-4-(In-methyl)phenylpyrrol-2-yl1oxamic acid (Ia),

(22) [3 cyano-4(p-methyl) phenylpyrrol-2-yl1oxamic acid (la),

(23) [3 cyano-4-rnethyl-4-phenylpyrrol-2-yl]oxamic acid (la),

(24) [3 cyano-4-methy1-4-(p-chloro)phenylpyrrol-2- y1]oxamic acid (Ia),

(25) [3-cyano-4-methyl-4-(p-fluoro)phenylpyrrol-2-yl] oxamic acid (Ia),

(26) [3 cyano-5-methyl-4-(p-bromo)phenylpyrr0l-2 yl]oxamic acid (Ia),

(27) [3 cyano-5-methyl-4- (m-chloro)phenylpyrrol-Z- yl]oxamic acid (Ia),

(28 [3-cyano-5-methyl-4- (o-fluoro) phenylpyrrol-Z-yl] oxamic acid (la),

(29) [3-cyano-5-methyl-4- (m-methoxy)phenylpyrrol-Z- yl]oxa.mic acid(Ia),

(30) [3-cyano-5-methyl-4- (p-methoxy) phenylpyrrol-Z- yl]oxamic acid(Ia),

(31) [3 cyano--rnethyl-4-(p-methyl)phenylpyrrol-2- yl]oxamic acid (Ia),

(32) [3-cyano 5 methy1-4-(p-ethyl)phenylpyrrol-2- yl]oxamic acid (Ia),

(33) [3 cyano-5-methyl-4-(m-methyl)phenylpyrrol-2- yl]oxamic acid (la),

(34) [3 cyano-5-methyl-4(o-methyl)phenylpyrrol-2- yl]oxamic acid (Ia),

(35) (3-cyano-4-methyl2-pyrryl)oxamic acid (Ia), etc.

Example 5 (3-cyano-4,5-dimethyl-l-phenylpyrrol-Z-yl) oxamic acid (Ia)and sodium salt (Ia) thereof (a) 3-anilino-2-butanone (IH) A mixture of21.5 g. (0.2 mole) of 3-hydroxy-2-butanone (IVa) (prepared as in Ann.436, 173), 18.63 g. (0.2 mole) of aniline (Nb) and 1 g. of formic acidis stirred and heated on a steam bath for about 1 hour. The mixture iscooled to room temperature, about 200 ml. of benzene added and themixture refluxed for about 4 hours. The reaction mixture is cooled toroom temperature where it remains for about 48 hours. The solution isevaporated to dryness and evaporated under vacuum to give 32.6 g. (100%yield) of an oil. Its distillation through a 6 inch Vigreux columnyields 23.8 g. of 3-anilino-2-butanone (V), a yellow oil boiling at 106C./0.5 mm. Hg. The infrared and nuclear magnetic resonance (NMR) spectraare in agreement with the proposed structure of the compound (V).

(b) 2-amino-3-cyano-4,5 -dimethyl-1-phenylpyrrole (H) To a solution of8.15 g. (0.05 mole) of 3-anilino-2- butanone (V) [prepared as in (a),above] in 50 ml. of methanol, cooled to 5 C. in an ice bath, 13.2 g.(0.2 mole) of malononitrile is added. The reaction mixture is stirred atroom temperature for about 15 minutes and at 50 C. in a water bath forabout 2 hours. The solution is cooled to room temperature and thenpoured into about 250 ml. of ice-Water. The resulting precipitate isfiltered to give 8.28 g. (78% yield) of material (II) melting at 125 to128 C. The white precipitate is recrystallized from ethanol-water togive 7.41 g. (70% yield) of colorless prisms of2-arnino-3-cyano-4,5-dimethyl-l-phenylpyrrole (H) melting at 125 to 126C. Ultraviolet absorption:

) dioxano max.

(c) Ethyl (3-cyano-4,5-dimethyl-l-phenylpyrrol-2-yl)oxamate (I) To asolution of 6.33 g. (0.03 mole) of 2-amino-3-cyano-4,5-dimethyl-l-phenylpyrrole (II) [obtained as in (b), above] in100 ml. of dry ethyl acetate (dried over a molecular sieve) and 3.03 g.(0.03 mole) of triethylamine, cooled to about 0 C. in an ice bath, asolution of 4.2 g. of ethyl oxalyl chloride dissolved in 25 ml. of dryethyl acetate is added dropwise. The mixture is stirred for about 1 hourat ice bath temperature, then for about 4 hours at room temperature andallowed to stand at room temperature for about 16 hours. The mixture isfiltered and the precipitate is washed with a small amount of dry ethylacetate. The filtrate is evaporated to dryness to yield an oily residueof ethyl (3-cyano-4,5-dimethy1-l-phenylpyrrol-Z-yl) oxamate (I)Following the procedure of (0), above, but substituting another alkyloxalyl halide for ethyl oxalyl chloride, such as (1) methyl oxalylchloride,

(2) propyl oxalyl fluoride,

(3) butyl oxalyl chloride,

(4) hexyl oxalyl fluoride, etc. yields, respectively,

(1) methyl (3-cyano-4,5-dimethyl 1 phenylpyrrOl-Z- yl)oxamate (I),

(2) propyl (3-cyano-4,5-dimethyl 1 phenylpyrrol-Z- yl)oxamate (I),

(3) butyl (3 cyano-4,5-dimethyl-l-phenylpyrrol-Z-yl) oxamate (I),

(4) hexyl (3 cyano-4,5-dimethyl-l-phenylpyrrol-Z-yl) oxamate (I), etc.

(d) (3-cyano-4,5-dimethyl-l-phenylpyrrol- 2-yl)oxarnic acid, sodium salt(Ia) A suspension of ethyl(3-cyano-4,S-dimethyl-l-phenylpyrrol-2-yl)oxamate (I) [obtained as in(c), above] and 60 ml. of 5% sodium hydroxide solution is stirred atroom temperature for about 2 hours. After treatment with Celite(diatomaceous earth) prior to filtration, the filtrate is evaporated todryness to give (3-cyano-4,5-dimethyl-1- phenylpyrrol-2-yl)oxamic acid,sodium salt (Ia).

Following the procedure of (d), above, but substituting anotherhydroxide (e.g., ammonium hydroxide, potassium hydroxide, or calciumhydroxide) for sodium hydroxide, yields a corresponding(3-cyano-4,5-dimethyl-l-phenylpyrrol-2-yl)oxamic acid, metal salt (Ia).

(e) (3-cyano-4,5-dimethyl-l-phenylpyrrol-2-yl)oxamic acid (Ia) Thefiltrate of (3-cyano-4,5-dimethyl-l-phenylpyrrol-Z- yl)oxamic acid,sodium salt (Ia), [from (d), above] is acidified with concentratedhydrochloric acid. The grey precipitate that forms is removed byfiltration and washed with Water. It is purified by dissolving inaqueous sodium bicarbonate solution, filtering the solution andreacidifying with 1N hydrochloric acid to give 3.51 g. of grey solid(3-cyano-4,5-dimethyl 1 phenylpyrrol-2-yl)oxamic acid (Ia), melting at189 C. (with decomposition). The infrared and NMR spectra are inagreement with the proposed structure of the compound (Ia).

Following the procedure of Example 5 but substituting another3-hydroxy-2-alkanone (IVa) for 3-hydroxy-2-butanone (IVa), such as (1)hydroxy-2-propanone (IVa) (prepared as in J. Chem. Soc. 59, 787),

(2) 3-hydroxy-2-pentanone (IVa) (prepared as in Bull. soc. chim. 39,216),

3) 3-hydroxy-2-hexanone (IVa) (prepared as in Bull. soc. roy. sci. Liege24, 2), etc.

yields, respectively,

1) (3-cyano-4-methyl 1 phenylpyrrol-Z-yDoxamic acid (Ia) and a metalsalt (Ia) thereof,

(2) (3-cyano-4-methyl 5 ethyl-l-phenylpyrrol-Z-yl) oxamic acid (Ia), anda metal salt (Ia) thereof,

(3) (3 cyano-4-methyl-5-propyl-l-phenylpyrrol-Z-yl) oxamic acid (Ia) anda metal salt (Ia) thereof, etc.

Following the procedure of Example 5 but substituting another amine(IVb) for aniline (IVb), such as (1) methylamine (IVb) [prepared as inOrg. Syn. 3, 67 (1923)],

(2) ethylamine (IVb) [prepared as in I Amer. Chem. Soc. 69, 836],

(3) propylamine (IVb) [prepared as in J. Amer. Chem. Soc. 74, 6824],

(4) butylamine (IVb) [prepared as in Org. Syn. coll. vol. 2, 319(1942)],

(5) pentylamine (IVb) [prepared as in J. Amer. Chem. Soc. 77, 2544],

(6) hexylamine (IVb) [prepared as in Ber. 43, 3599],

(7) o-bromoaniline (IV [prepared as in J. Chem. Soc. 1925, 494],

(8) m-bromoaniline (IVb) [prepared as in Bull. soc. chim. 7, 955],

(9) p-bromoaniline (IVb) [prepared as in Gazz. Chim. ital. 58, 233],

(10) o-chloroaniline (IVb) [prepared as in J. Chem. Soc. 1921, 1013],

(11) m-chloroaniline (IVb) (ibid.),

(12) p-chloroaniline (IVb)( ibid.),

13) o-fluoroaniline (IVb) [prepared as in Ber. 64, 2469],

(14) m-fiuoroaniline (IVb) (prepared as in J. Chem. Soc. 1928, 421),

15) p-fiuoroaniline (IVb) (prepared as in Ber. 62, 3041),

(16) o-methoxyaniline (IVb) [prepared as in Chem. Zentr. I, 3317(1926)],

(17) m-methoxyaniline (IVb) (prepared as in Ber. 47, 1537),

(18) p-methoxyaniline (IVb) (prepared as in J. Org. Chem. 9, 1),

(19) o-methylaniline (or o-toluidine) (prepared as in J. Amer. Chem.Soc. 48, 2163 (20) m-methylaniline (or m-toluidine) (prepared as in Ber.22, 840),

(21) p-methylaniline (or p-tolnidine) (prepared as in Rec. trav. chim.28, 109),

(22) a, x,u-trifluoro-o-toluidine (or o-trifluoromethylaniline)(prepared as in French Patent 805,704),

(23) a,a,a-trifiuoro-m-toluidine (or m-trifluoromethylaniline) (preparedas in J. Amer. Chem. Soc. 68, 1602),

(24) o ,a-trifluoro-p-toluidine (or p-trifluoromethylaniline) (preparedas in Rec. trav. chim. 28, 109), etc., yields, respectively,

(1) (3 cyano 4,5 dimethyl 1 methylpyrrol-Z-yl) oxamic acid (Ia) and ametal salt thereof (Ia),

(2) (3 cyano 4,5 dimethyl 1 ethylpyrrol-Z-yl) oxamic acid (Ia) and ametal salt (Ia) thereof,

(3) (3 cyano 4,5 dimethyl 1 propylpyrrol-Z-yl) oxamic acid (Ia) and ametal salt (Ia) thereof,

(4) (3 cyano 4,5 dimethyl 1 butylpyrrol-2-yl) oxamic acid (Ia) and ametal salt (Ia) thereof,

(3 cyano 4,5 dimethyl 1 pentylpyrrol-Z-yl) oxamic acid (Ia) and a metalsalt (Ia) thereof,

(6) (3 cyano 4,5 dimethyl 1 hexylpyrrol-Z-yl) oxamic acid (Ia) and ametal salt (Ia) thereof,

(7) [3 cyano 4,5 dimethyl 1 (o-bromoanilino) pyrrol 2 yl]oxamic acid(Ia) and a metal salt (Ia) thereof,

(8) [3 cyano 4,5 dimethyl 1 (rnbromoanilino) pyrrol 2 yl]oxamic acid(Ia) and a metal salt (Ia) thereof,

(9) [3 cyano 4,5 dimethyl 1 (p-bromoanilino) pyrrol 2 yl]oxamic acid(Ia) and a metal salt (Ia) thereof,

[3 cyano 4,5 dimethyl 1 (o-chloroanilino) pyrrol 2 y1]oxamic acid (Ia)and a metal salt (Ia) thereof,

(11) [3 cyano 4,5 dimethyl 1 (m-chloroanilino) pyrrol 2 yl]oxamic acid(Ia) and a metal salt (Ia) thereof,

(12) [3 cyano 4,5 dimethyl 1 (p-chloroanilino) pyrrol 2 yl]oxamic acid(Ia) and a metal salt (Ia) thereof,

(13) [3 cyano 4,5 dimethyl 1 (o-fluoroanilino) pyrrol 2 yl]oxamic acid(Ia) and a metal salt (Ia) thereof,

(14) [3 cyano 4,5 dimethyl 1 (m-fiuoroanilino) pyrrol 2 yl]oxamic acid(Ia) and a metal salt (Ia) thereof,

[3 cyano 4,5 dimethyl 1 (p-fluoroanilino) pyrrol 2 yl]oxamic acid (Ia)and a metal salt (Ia) thereof,

(16) [3 cyano 4,5 dimethyl 1 (o-methoxyanilino)pyrrol 2 yl]oxamic acid(Ia) and a metal salt (Ia) thereof,

(17) [3 cyano 4,5 dimethyl 1 (m-methoxyanilino)pyrrol 2 ]oxamic acid(Ia) and a metal salt (Ia) thereof,

(18) [3 cyano 4,5 dimethyl 1 (p-methoxyam'- lino)pyrrol 2 yl]oxamic acid(Ia) and a metal salt (Ia) thereof,

(19) [3 cyano 4,5 dimethyl 1 (o-methylanilino) pyrrol 2 yl]oxamic acid(Ia) and a metal salt (Ia) thereof,

(20) [3 cyano 4,5 dimethyl-1-(m-methylanilino) pyrrol 2 yl]oxamic acid(Ia) and a metal salt (Ia) thereof,

(21) [3 cyano 4,5 dimethyl 1 (p-methylanilino) pyrrol 2 yl]oxamic acid(Ia) and a metal salt (Ia) thereof,

(22) [3 cyano 4,5 dimethyl 1 (cz,oz,a-ififiLIOIO-O toluidino)pyrrol 2yl]oxamic acid (Ia) and a metal salt (Ia) thereof,

23) [3 cyano 4,5 dimethyl 1 (a,u,:x-trifluor0-mtolnidino)pyrrol 2yl]oxamic acid (Ia) and a metal salt (Ia) thereof,

(24) [3 cyano 4,5 dimethyl 1 (a,x,a-trifiuorop-toluidino)pyrrol-2-yl]oxamic acid (Ia) and a metal salt(Ia) thereof, etc.

Following the procedure of Example 5 but substituting another3-hydroXy-2-alkan0ne (IVa) for 3-hydr0Xy-2-butanone (IVa) and anotheramine (IVb) for aniline (IVb), such as 1) hydroxy 2 propanone (IVa) andbutylamine hydroxy 2 propanone (IVa) and hexylamine (3) hydroxy 2propanone (IVa) and o-bromoaniline (IVb),

(4) hydroxy 2 propanone (IVa) and m-chloroaniline (IVb),

(1)) hydroxy 2 propanone (IVa) and p-fiuoraniline (6) hydroxy 2propanone (IVa) and o-methoxyaniline (IVb),

(7 hydroxy 2 propanone (IVa) and m-methylaniline (IVb),

(8) hydroxy 2-propanone (IVa) and oc,oz,oz-tl'ifil.1OIO-O- toluidine,

( 3-hydroxy 2 pentanone (IVa) and propylamine (10) 3 hydroxy 2 pentanone(IVa) and pentylamine (IVb),

(11) 3 hydroxy 2 pentanone (IVa) and p-bromoaniline (IVb),

12) 3 hydroxy 2 pentanone (Na) and o-chloroaniline (IV b),

(13) 3 hydroxy 2 pentanone (IVa) and m-fiuoroaniline (IVb),

(14) 3 hydroxy Z-pentanone (IVa) and p-methoxyaniline (IVb),

(15 3 hydroxy 2 pentanone (IVa) and o-methylaniline (IVb),

(16) 3 hydroxy 2 pentanone (IVa) and a,a,a-trifluoro-m-toluidine (IVb),

(17) 3 hydroxy 2 hexanone (IVa) and methylamine (IVb),

( (18) 3 hydroxy 2 hexanone (IVa) and ethylamine IVb),

(19) 3 hydroxy 2 hexanone (IVa) and m-bromoaniline (IVb),

(20) 3 hydroxy 2 hexanone (IVb) and p-chloroaniline (IVb),

(21) 3 hydroxy 2 hexanone (IVa) and o-fluoroaniline (IVb),

(22) 3 hydroxy 2-hexanone (IVa) and m-methoxw aniline (IVb),

21 (23) 3 hydroxy 2 hexanone (Na) and p-methylaniline (IVb),

(24) 3 hydroxy 2 hexanone (Na) and a,ot,ot-tlifluoro-p-toluidine (IVb),etc.

yields, respectively,

(1) (3 cyano 4 methyl 1 butylpyrrol 2 yl) oxamic acid (Ia) and a metalsalt (Ia) thereof,

(2) (3-cyano 4 methyl-l-hexylpyrrol-Z-yl)oxamic acid (Ia) and a metalsalt (Ia) thereof,

(3) [3-cyano 4 methyl-1-(o-bromoanilino)pyrrol- 2-yl]oxamic acid (Ia)and a metal salt (Ia) thereof,

(4) [3-cyano 4 methyl-l-(m-chloroanilino)pyrrol- 2-yl]ox'amic acid -(Ia)and a metal salt (Ia) thereof,

(5) [3-cyano 4 methyl-1-(p-flu'oroanilino)pyrrol-2- yl]oxamic acid (Ia)and a metal salt (Ia) thereof,

(6) [3-cyano 4 methyl-1-(o-methoxyanilino)pyrrol- 2-yl]oxamic acid (Ia)and a met-a1 salt (I-a) thereof,

(7) [3-cyano 4 methyl-l-(m-methylanilino)pyrro1- 2-yl1oxamic acid (Ia)and a metal salt (Ia) thereof,

(8) [3-cyano 4 methyl-l-(a,a,a-trifluoro-o-toluidino) pyrrol-2-yl1oxamicacid (Ia) and a metal salt (Ia) thereof,

(9) (3-cyano 4 methyl-S-ethyl-l-propylpyrrol-Z-yl) oxamic acid (Ia) anda metal salt (Ia) thereof,

(10) (3-cyano 4 methyl-S-ethyl-l-pentylpyrrol-Z- yl)oxamic acid (Ia) anda metal salt (Ia) thereof,

(11) [3-cyano 4 methyl-S-ethyl-l- (p-bromoanilino) pyrrol-2-yl]oxamicacid (Ia) and a metal salt (Ia) thereof,

(12) [3-cyano 4 methyl-S-ethyl-l-(o-chloroanilino) pyrrol-2-yl]oxamicacid (Ia) and a metal salt (Ia) thereof,

(13) [3-cyan0 4 methyl-S-ethyl-l-(m-fiuoroanilino) pyrrol-2-yl1oxamicacid (Ia) and a metal salt (Ia) thereof,

(14) [3-cyano 4 methyl-S-ethyl-l-(p-methoxyanilino)pyrrol-2-yl]oxamicacid (Ia) and a metal salt (Ia) thereof,

(15) [3-cyano 4 methyl-S-ethyl-l-(o-methylanilino) pyrrol-2-yl1oxamicacid (Ia) and a metal salt (Ia) thereof,

(16) [3-cyano 4methyl-S-ethyl-l-(a,x,a-trifiuorom-toluidino)pyrrol-2-yl]oxamic acid(Ia) and a metal salt thereof,

(17) (3-cyano 4 methyl-S-propyl-l-methylpyrrol- 2-yl)oxamic acid (Ia)and a metal salt (la) thereof,

(18) (3-cyano 4 methyl-S-propyl-l-ethylpyrrol-Z- yl)oxamic acid (Ia) anda metal salt (Ia) thereof,

(19) [3 cyano-4-methyl-5-propyl-1-(m-bromoanilin-o) pyrrol-2-yl1oxamicacid (Ia) and a metal salt (Ia) thereof,

(20) [3-cyano 4 methyl-S-propyl-l-(p-chloroanilino)pyrrol-2-yl]oxamicacid (Ia) and a metal salt (Ia) thereof,

-(21) [3-cyano-4 methyl-S-propyl-l-( o-fluoroanilino) pyrrol-2-yl1oxamicacid (Ia) and a metal salt (Ia) thereof,

(22) [3-cyano 4 methyl-S-propyl-l-(m-methoxyanilino)propyl-2-yl]oxamicacid (Ia) and a metal salt (Ia) thereof,

(23) [3-cyano 4 methyl-S-propyl-l-(p-methylanllino)pyrrol-2-yl]oxamicacid (Ia) and a metal salt (Ia) thereof,

(24) [3-cyano 4methyl-S-propyl-l-(a,a,u-trifluorop-toluidino)pyrrol-2-yl]oxamic acid(Ia) and a metal salt (Ia) thereof, etc.

The compositions of the present invention are presented foradministration to humans and animals in unit dosage forms, such astablets, capsules, pills, powders, granules, suppositories, syrups,elixirs, drops, sterile parenteral solutions or suspensions, and oralsolutions or suspensions, and oil-in-water and water-in-oil emulsionscontaining suitable quantities of the compound of Formula Ia. Thepreferred method of administration is by inhalation into the lung bymeans of a liquid aerosol or powder for insufilation.

For oral administration either solid or fluid unit dosage forms can beprepared. For preparing solid compositions such as tablets, the compoundof Formula la is mixed with conventional ingredients such as tale,magnesium stearate, dicalcium phosphate, magnesium aluminum silicate,calcium sulfate, starch, lactose, acacia, methylcellulose, andfunctionally similar materials as pharmaceutical diluents or carriers.Capsules are prepared by mixing the compound with an inertpharmaceutical diluent and filling the mixture into a hard gelatincapsule of appropriate size. Soft getlatin capsules are prepared bymachine encapsulation of a slurry of the compound with an acceptablevegetable oil, light liquid petrolatum or other inert oil.

Fluid unit dosage forms for oral administration such as syrups, elixirs,and suspensions can be prepared. The water-soluble forms can bedissolved in an aqueous vehicle together with sugar, aromatic flavoringagents and preservatives to form a syrup. An elixir is prepared by usinga hydro-alcoholic (ethanol) vehicle with suitable sweeteners such assugar and saccharin, together with an aromatic flavoring agent.

Suspensions can be prepared in an aqueous vehicle with the aid ofasuspending agent such as acacia, tragacanth, methylcellulose and thelike.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, water being preferred. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle. In preparing solutions thecompound can be dissolved in water for injection and filter sterilizedbefore filling into a suitable vial or ampul and sealing.Advantageously, adjuvants such as a local anesthetic, preservative andbufiering agents can be dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum. The dry lyophilized powder is thensealed in the vial and an accompanying vial of water for injection issupplied to reconstitute the liquid prior to use. Parenteral suspensionsare prepared in substantially the same manner except that the compoundis suspended in the vehicle instead of being dissolved and sterilizationcannot be accomplished by filtration. The compound can be sterilized byexposure to ethylene oxide before suspending in the sterile vehicle.Advantageously, a surfactant or wetting agent is included in thecomposition to facilitate uniform distribution of the compound.

The preferred compositions are those adapted for in halation into thelung and containing a water soluble form of a compound of Formula Ia.

Compositions for inhalation are of three basic types: (1) a powdermixture preferably micro-pulverized; (2) an aqueous solution to besprayed with a nebulizer; and (3) an aerosol with volatile propellant ina pressurized container.

The powders are quite simply prepared by mixing a compound of Formula Iawith a solid diluent which is compatible with lung tissue, preferablylactose. The powders are packaged in a device adapted to emit a measured amount of powder when inhaled through the mouth.

Aqueous solutions are prepared by dissolving the compound of Formula Iawhere M is aluminium, ammonium, sodium, potassium ortris-(hydroxymethyl)methyl ammonium in water and adding salt to providean isotonic solution and buffering to a pH compatible with inhalation.The solutions are dispersed in a spray device or nebulizer and sprayedinto the mouth while inhaling.

Aerosols are prepared by dissolving a compound of Formula Ia whereM-aluminum, ammonium, sodium potassium or tris(hydroxymethyl)methylammonium in water or ethanol and mixing with a volatile propellant 23and placing in a pressurized container having a metering valve torelease a predetermined amonut of material.

The liquefied propellant employed is one which has a boiling point 65 F.at atmospheric pressure. For use in compositions intended to produceaerosols for medicinal or cosmetic use, the liquefied propellant shouldbe 110111 toxic. Among the suitable liquefied propellants which may beemployed are the lower alkanes containing up to five carbon atoms, suchas butane and pentane, or a lower alkyl chloride, such as methyl, ethyl,or propyl chlorides. Suitable liquefied propellants are the fiuorinatedand fluorochlorinated lower alkanes such as are sold under thetrademarks Freon and Genetron. Mixtures of the abovementionedpropellants may suitably be employed. Examples of these propellants aredichlorodifluoromethane (Freon 12.) dichlorotetrafluoroethane (Freon114), trichloromonofluoromethane (Freon ll), dichloromonofluoromethane(Freon 21) monochlorodifiuoromethane (Econ 22), trichlorotrifluoroethane(Freon 113), difluoroethane (Genetron 142A) andmonochlorotrifiuoromethane (Freon 13). Alternatively, the inhalationcompositions of this invention can be dispensed from pressure-loadedvessels, e.g., by use of compressed air or carbon dioxide cartridges.

The term unit dosage form, as used in the specification and claims,refers to physically discrete units suitable as unitary dosages forhuman subjects and animals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticaldiluent, carrier, or vehicle. The specification for the novel unitdosage forms of this invention are dictated by and directly dependent on(a) the unique characteristics of the active material and the particulareffect to be achieved and (b) the limitations inherent in the art ofcompounding such an active material for use in humans and animals, asdisclosed in detail in this specification, these being features of thepresent invention. Examples of suitable unit dosage forms in accord withthis invention are tablets, capsules, pills, suppositories, powderpackets, granules, Wafers, cachets, teaspoonfuls, tablespoonfuls,dropperfuls, ampuls, vials, aerosols with metered discharges, segregatedmultiples of the foregoing, and other forms as herein described. Y

The dosage of the compound of Formula Ia for treatment depends on theroute of administration. A dosage schedule of from about 0.1 to 50 mg.in a single dose, administered parenterally or by inhalation, embracesthe effective range for preventing allergic attack for which thecompositions are effective. The dosage to be administered is repeated upto 6 times daily. The oral dose is from about 0.1 to about 500 mg. in asingle dose.

Alternatively, the compounds of Formula Ia in suitable pharmaceuticalcompositions can be administered first as a priming dose to adequatelymitigate and control the allergic symptoms, followed by maintenancedoses consisting of dosages of much reduced amounts of drugs, e.g., fromabout th to about 36 111 of the amounts of drug of the priming dose,preferably from about /5 th to about th, in a suitable pharmaceuticalcomposition and at suitable intervals, e.g., 4 times daily, to maintainthe antiallergic prophylaxis, as prescribed by the attending phySi-Ecran.

The administration of the compositions of the present invention tohumans and animals provides a method for the prophylactic treatment ofallergy for all anaphylactic reactions of a reaginand non-reaginmediated nature. That is to say, these compositions when administered toa sensitized individual prior to the time that the individual comes intocontact with substances to which he is allergic, the compositions willprevent the allergic reaction which would otherwise occur.

For example, the process can be used for prophylactic treatment of suchchronic condiitons as bronchial asthma,

allergic rhinitis, food allergy, hay fever, urticaria, and auto-immunediseases.

Example 6 A lot of 10,000 tablets, each containing 0.1 mg. of(3-cyano-4,S-dimethyl-Z-pyrryl)oxamic acid, sodium salt (la) is preparedfrom the following types and amounts of ingredients:

(3-Cyano-4,5-dimethyl-2-pyrryl)oxamic acid, so-

dium salt (la) 1 Dicalci-um phosphate 1,500 Methylcellulose, U.S. P. (l5cps.) 60 Talc 150 Corn Starch 200 Calcium stearate 12 Example 7 Onethousand two-piece hard gelatin capsules, each containing mg. of(3-cyano-4,S-dimethyl-Z-pyrryl)- oxamic acid, sodium salt (Ia) areprepared from the following types and amounts of ingredients:

(3-cyano-4,5-dimethyl-2-pyrryl)oxamic acid, sodium salt (Ia), micronized100 Talc 10 Magnesium stearate 0.5

The ingredients are mixed well and filled into capsules of the propersize.

Capsules so prepared are useful in preventing attacks of bronchialasthma at a dose of one capsule every 4 to 6 hours.

Example 8 One thousand tablets, each containing 500 mg. of (3-cyano-4,5-dimethyl-2-pyrryl)oxamic acid, sodium salt (Ia) are made fromthe following types and amounts of ingredients:

Gm. (3-cyano-4,5-dimethyl-2-pyrryl)oxamic acid, sodium salt (.Ia) 500Microcrystalline cellulose NF Starch 16 Magnesium stearate powder 4 Theingredients are screened and blended together and pressed into 640 mg.tablets.

The tablets are useful to protect against food allergy at a dose of 1tablet before meals.

Example 9 A sterile preparation suitable for intramuscular injection andcontaining 1 mg. of (3-cyano-4,5-dimethyl-2- pyrryl)oxarnic acid, sodiumsalt (Ia) in each milliliter is prepared from the following ingredients:

(3-cyano-4,5-dimethyl-Z-pyrryl)oxamic acid, sodium salt (Ia) em 1 Benzylbenzoate cm 200 Methylparaben gm 1.5 Propylparaben cm 0.5 Cottonseed oilq.s ..ml 1,000

One milliliter of this sterile preparation is injected intramuscularlyfor prophylactic treatment of allergic rhinitis.

Example 10 Aqueous Solution 600 ml. of an aqueous solution containing0.1 mg. of ('3-cyano-4,5-dimethyl-2-pyrryl)oxamic acid, sodium salt (Ia)per ml. is prepared as follows:

(3-cyano-4,5-dimethyl-2-pyrryl)oxamic acid, sodium salt (Ia) mg.. 60Sodium chloride mg 5,400 Water for injection q.s. ml 600 Example 11Powder for Insutfiation A powder mixture consisting of 100 mg. of(3-cyano- 4,5-dimethyl-2-pyrryl)oxamic acid, sodium salt (Ia) andsufficient lactose to make grams of mixture is micropulverized andplaced in an insutfiator designed to deliver 50 mg. of powder per dose.

The powder is inhaled into the lungs for prevention of asthmaticattacks.

Example 12 Aerosol Twelve grams of an aerosol composition is preparedfrom the following ingredients:

(3-cyano-4,5dimethyl-2-pyrryl)-oxamic acid, sodium salt (Ia) 0.015 50%ethanol 4.855 Freon 12 1.43 Freon 114 5.70

The oxamic acid, sodium salt (la) is dissolved in the 50% ethanol andchilled to -30 C. and added to the chilled Freons. The 12 grams ofcomposition is added to a 13 cc. plastic coated bottle and capped with ametering valve. The metering valve releases 80 mg. of composition in anaerosol.

The aerosol is inhaled every 4 to 6 hours for prevention of asthmaticattacks.

Following the procedure of Example 12, but substituting an appropriateamount of the THAM salt of (3- cyano-4,5-dimethyl-2-pyrryl)oxamic acid(Ia), gives an aerosol that can be similarly employed.

The procedures described above in Examples 6 through 12 for thepreparation of the compositions of (3-cyano-4,5-dirnethyl-2-pyrryl)oxamic acid, sodium salt (1a), can also beemployed in the production of medicaments wherein the active ingredientis another compound embraced by Formula Ia, e.g.,

(3-cyano-4,5-diethyl-2-pyrryl)oxamic acid, sodium salt(3-cyano-4,5-dipropyl-2-pyrryl)oxamic acid, sodium salt(3-cyano-4,S-dibutyl-Z-pyrryl)oxamic acid, sodium salt(3-cyano-4,S-dibutyl-Z-pyrryl) oxamic acid, potassium salt (Ia),

(3-cyano-4,5-diisopropyl-2-pyrryl)-oxamic acid, sodium salt (Ia),

(3-cyano-4,5-dipentyl-2-pyrryl)oxamic acid, sodium salt(3-cyano-4,S-dihexyl-2-pyrryl)oxamic acid, ammonium salt (Ia),

(3-cyano-4,S-diisobutyl-Z-pyrryl)oxamic acid, ammonium salt (Ia),

(3-cyano-4-phenylpyrrol-2-yl)oxamic acid, potassium salt (Ia),

[3-cyano-4-(p-bromo)phenylpyrrol-Z-yl]oxamic acid,

potassium salt (Ia),

[3-cyano-4- (p-chloro phenylpyrrol-Z-yl] oxamic acid,

potassium salt (Ia),

[3-cyano-4- (p-fluoro)phenylpyrrole-2-yl]oxamic acid,

potassium salt (Ia),

[3-cyano-4- (m-chloro) phenylpyrrol-Z-yl] oxamic acid,

calcium salt (Ia),

[3-cyano-4-(o-fluoro)phenylpyrrol-Z-yl] oxamic acid,

calcium salt (Ia),

[3-cyano-4-(o-methoxy)phenylpyrrol-Z-yl] oxamic acid,

calcium salt (Ia),

[3-cyano-4- (p-methoxy) phenylpyrrol-2-y11oxamic acid,

ammonium salt (Ia),

[3-cyano-4- (p-methoxy) -phenylpyrrol-2-yl] oxamic acid,

sodium salt (Ia),

[3-cyano4- (o-methyl) phenylpyrrol-Z-yl] oxamic acid,

sodium salt (Ia),

[3-cyano-4- (m-methyl) phenylpyrrol-Z-yl] oxamic acid,

sodium salt (Ia),

(3-cyano-S-methyl-4-phenylpyrrol-2-yl)oxamic acid,

sodium salt (Ia),

[3-cyano-5-methyl-4- (o-chloro -phenylpyrrol-2-yl] oxamic acid, ammoniumsalt (la),

[3 -cyano-5-methyl-4- p-fluoro )phenylpyrrol-Z-yl] oxamic acid, sodiumsalt (Ia),

[3-cyano-5-methyl-4- (o-methoxy) phenylpyrrol-Z-yl] oxamic acid, calciumsalt (la),

[3 -cyano-5-rnethyl-4- (m-methyl phenylpyrrol-Z-yl] oxamic acid, sodiumsalt (Ia),

[3-cyano-5-methyl-4- (p-methyl) phenylpyrrol-Z-yl] oxamic acid,potassium salt (Ia),

[3-cyano-5-methyl-4- (o-ethyl) phenylpyrrol-Z-yl] oxamic acid, calciumsalt (Ia),

[3-cyano-5-methyl-4-(m-methyl)phenylpyrrol-Z-yl] oxamic acid, ammoniumsalt (Ia),

(3-cyano-4,S-dimethylpyrrol-Z-yl)oxamic acid, THAM salt (Ia),

(3-cyano-4,5dipropylpyrrol-2-yl)oxamic acid THAM salt (Ia),

(3-cyano-4,5-diisobutylpyrrol-2-y1)-oxamic acid, THAM salt (Ia),

(3-cyano-4-phenylpyrrol-2-yl)-oxamic acid, THAM salt [3-cyano-4-(p-chloro)phenylpyrrol-2-yl1oxamic acid,

THAM salt (Ia),

[3-cyano-4- (p-fluoro) phenylpyrrol-2-yl] oxamic acid,

THAM salt (Ia),

[3-cyano-4- (o-methoxy) phenylpyrrol-Z-yl) oxamic acid,

THAM salt (Ia),

[3-cyano-4-(m-methyl)phenylpyrrol-Z-yl] oxamic acid,

THAM salt (Ia),

(3-cyano-5-methyl-4-phenylpyrro1-2-yl)-oxamic acid,

THAM salt (Ia),

[3-cyano-5-methyl-4- (p-fluoro) -phenylpyrrol-2-yl] oxamic acid, THAMsalt (Ia),

[3-cyano-5-methyl-4- (p-methyl) phenylpyrrol-Z-yl] oxamic acid, THAMsalt (Ia),

(3-cyano-4,5-dimethyl-l-phenylpyrrol-Z-yl) oxamic acid(3-cyano-4,5-dimethyl-l-phenylpyrrol-Z-yl) oxamic acid,

sodium salt (Ia),

(3-cyano-4,5-dimethyl-l-phenylpyrrol-Z-yl) oxamic acid,

calcium salt (Ia),

(3-cyano-4-methyl-l-phenylpyrrol-Z-yl)oxamic acid(3-cyano-4-methyl-5-ethyll-phenylpyrrol-Z-yl) oxamic acid (Ia),

(3-cyano-4-methyl-S-propyl-l-phenylpyrrol-Z-yl) oxamic acid, ammoniumsalt (Ia),

(3-cyano-4,5-dimethyl-1-methylpyrrol-2-yl)oxamic acid(3-cyano-4,5-dimethyl-l-propylpyrrol-2-yl)oxamic acid,

calcium salt (Ia),

(3-cyano-4,5-dimethyl-l-pentylpyrrol-Z-yl)oxamic acid[3-cyano-4,5-dimethyl-1-(o-bromoanilino)pyrrol-Z-yl] oxamic acid, THAMsalt (Ia),

[3-cyano-4,5-dimethyl- 1- (m-chloroanilino pyrrol-Z-yl] oxamic acid,THAM salt (la),

[3 -cyan-4,5-dimethyl-1- (p-fiuoroanilino pyrrol-Z-yl] oxamic acid,potassium salt (Ia),

[3-cyano-4,5-dimethyl-1- o-methoxyanilino) pyrrol-Z-yl} oxamic acid,THAM salt (1a),

[3 -cyano-4,5-dimethyl- 1 o-methoxyanilino pyrrol-2-yl] oxamic acid,THAM salt (Ia),

[3-cyano-4,5-dimethyl1-(u,a,a-trifluoro-o-toluidino) pyrrol-2-yl1oxamicacid, sodium salt (Ia),

[3-cyano-4-methyl-l-butylpyrrol-Z-yl]oxamic acid, THAM salt (Ia),

[3-cyano-4-methy1- 1- (o-bromoanilino pyrrol-Z-yl] oxamic acid, THAMsalt (Ia),

[3-cyano-4-methyl- 1- (m-methoxyanilino) pyrrol-Z-yl] oxamic acid, THAMsalt (Ia),

[3-cyan0-4-methyl- 1- (p-methylanilino pyrrol-Z-yl oxamic acid, THAMsalt (Ia),

[3-cyano-4-methyl- 1- a,mot-itifillOIO-P-tOlUidiIlO)py11'012- yl]oxamicacid, THAM salt (Ia),

(3-cyano-4-methyl-S-ethyl-l-propylpyrrol-2-y1] oxamic acid, THAM salt(Ia),

[3-cyano-4-methyl-S-ethyl-l-(o-chloroanilino)pyrrol-Z- yljoxamic acid,sodium salt (Ia),

[3-cyano-4-methyl-S-ethyll- (m-methoxyanilino) pyrrol- 2-yl]oxamic acid,THAM salt (Ia),

[3-cyano-4-methyl-5-ethyl- 1- (p-methylanilino pyrrol-2- yl]oxamic acid,THAM salt (la),

(3 -cyano-4-methyl-S-propyll-e thylpyrrol-Z-yl) oxamic acid, THAM salt(Ia),

[3-cyano-4-methyl-5-propyl- 1- (o-fluoroanilino) pyrrol-Z- yl] oxamicacid, THAM salt (Ia),

[3-cyano-4-methyl-5-propyl- 1- (m-methoxyanilino) pyrrol- 2-yl]oxamicacid, ammonium salt (la),

[3 -cyano-4-methyl-5-propyl-1- p-methylanilino pyrrol-Z- yl]oxamic acid,THAM salt (Ia),

[3-cyano-4-methyl-5-propyl-1- a,a,a-trifluoro-m-toluidino)pyrrol-2-yl10xamic acid, T HAM salt (Ia),

etc.

While the treatment of hay fever, bronchial asthma, food allergy,allergic rhinitis and asthmatic attacks disclosed following Examples 6through 12 utilizes (3-cyano- 4,5-dimethyl-2-pyrryl)oxamic acid, sodiumsalt (Ia), similarly efiective therapy is provided with comparabledosages by employing medicaments wherein the active ingredient isanother compound embraced by Formula Ia, e,g.,

(3-cyano4,5-diethyl2-pyrryl)oxamic acid, sodium salt(3-cyano-4,S-dipropyl-Z-pyrryl)oxamic acid, sodium salt(3-cyario-4,5-dimethyl-2-pyrryl)oxamic acid, sodium salt(3-cyano-4,5-dipentyl-2-pyrryl)oxamic acid sodium salt(3-cyano-4,S-diisopropyl-Z-pyrryl)oxamic acid, sodium salt (Ia),

(3-cyano-4,5-dibutyl-Z-pyrryl)oxamic acid, THAM salt(3-cyano-4-phenylpyrrol-2-yl)oxamic acid, ammonium salt (Ia),

[3-cyano-4- (o-chloro) phenylpyrrol-2-yl1oxamic acid,

ammonium salt (Ia),

[3-cyano-4-(m-fluoro)phenylpyrrol-Z-yl]oxamic acid,

potassium salt (Ia),

[3-cyano-4- (p-bromo)-pl1enylpyrr0l2-yl]oxamic acid,

potassium salt (Ia),

[3-cyano-4- (o-methoxy)phenylpyrrol-2-yl1oxamic acid,

calcium salt (Ia),

[3-cyano-4- (m-ethoxy phenylpyrrol-2-yl1oxamic acid,

calcium salt (Ia),

[3-cyano-4- (p-methyl phenylpyrrol-2-yl1oxamic acid,

ammonium salt (Ia),

[3-cyano-4-(o-methyl -phenylpyrrol-2-yl] oxamic acid,

sodium salt (Ia),

( 3-cyanoS-methyl-4-phenylpyrrol-2-yl oxamic acid,

potassium salt (Ia),

(3-cyano-5-methyl-4-phenylpyrrol-2-y1)oxamic acid,

calcium salt (la),

[3 -cyano-5-methyl-4- o-bromo phenylpyrrol-Z-yl] oxamic acid, calciumsalt (Ia),

[3-cyano-5-methyl-4- (m-chloro)phenylpyrrol-2-yl1oxamic acid, calciumsalt (Ia),

[3-cyano-5-methyl-4-(o-methoxy)phenylpyrrol-Z-yl] oxamic acid, ammoniumsalt (Ia),

[3-cyano-5-methyl-4- (m-methoxy) phenylpyrrol-Z-yl] oxamic acid,ammonium salt (Ia),

[3-cyano-5-methyl-4- (p-methyl phenylpyrrol-Z-yl] oxamic acid, sodiumsalt (Ia),

E 3 cyano-5-methyl-4- (o-methyl) phenylpyrrol-Z-yl] oxamic acid, sodiumsalt (Ia),

(3-cyano-4-ethyl-2-pyrryl)oxamic acid, potassium salt(3-cyano-4-methyl-2-pyrryl)oxamic acid, potassium salt(3-cyano-4,S-diethylpyrrol-Z-yl)oxamic acid, THAM salt(3-cyano-4,5-dipropylpyrrol-2-yl)oxamic acid, THAM salt (Ia),

(3-cyano-4,5-dipentylpyrrol-2-yl)oxamic acid, THAM salt (Ia),

(3-cyano-4-phenylpyrrol-2-yl)oxamic acid, THAM salt[3-cyano-4(o-flu0ro)phenylpyrrol-Z-yl]oxamic acid,

THAM salt (Ia),

[3cyano-4- (m-methoxy)phenylpyrrol-Z-yl] oxamic acid,

THAM salt (Ia),

[3-cyano-4- (p-methyl) phenylpyrrol-Z-yl] oxamic acid,

THAM salt (Ia),

(3-cyano-S-methyl-4-phenyl-pyrrol-2-yl)oxamic acid,

THAM salt (Ia),

[3 -cyano-5-methyl-4 (o-fiuoro phenylpyrrol-Z-yl] oxamic acid, THAM salt(Ia),

[3 -cy ano-5-methyl-4- (m-methoxy) phenylpyrrol- 2-yl] oxamic acid, THAMsalt (Ia),

[3-cyano-5 -methyl- 4- p-methyl phenylpyrrol-Z-yl] oxamic acid, THAMsalt (Ia),

(32cyano-4-methyl-2-pyrrol)oxamic acid, THAM salt(3-cyano-4,5-dimethyl-l-phenylpyrrol-Z-yl)oxamic acid,

THAM salt (Ia),

( 3-cyano-4,5-dimethyl-l-phenylpyrrol-Z-yl) oxamic acid,

potassium salt (Ia),

(3-cyano-4-methyl-1-phenylpyrrol-2-yl) oxamic acid,

THAM salt (Ia),

(3-cyan0-4-methyl-5-ethyl-l-phenylpyrrol-Z-yl) oxamic acid, THAM salt(Ia),

(3-cyano-4-methyl-5-ethyl-l-phenylpyrrol-2-yl)oxamic acid, sodium salt(Ia),

(3-cyano-4-methyl-5-propyl-l-phenylpyrrol-Z-yl)oxamic acid, THAM salt(Ia),

( 3-cyano-4,5-dimethyll-ethylpyrrol-Z-yl) oxamic acid,

THAM salt (Ia),

(3-cyano-4,5-dimethyl-1-pr0pylpyrrol-2-yl)oxamic acid,

ammonium salt (Ia),

(3-cyano-4,5-dimethyll-hexylpyrrol-Z-yl)oxamic acid,

THAM salt (Ia),

[3-cyano-4,5-dimethyl- 1- (o-chloro anilino pyrrol-2-yl1 oxamic acid, THAM salt (Ia),

[3-cyano-4,S-dimethyl-1-(m-methoxyanilino)pyrrol-Z- ylloxamic acid, THAMsalt (Ia),

29 [3-cyano-4,5-dimethyl-1-(p-methylanilino)pyrrol-2-yl] oxamic acid,THAM salt (Ia), [3-cyano-4,5-dimethyl-1-(a, x,a-trifluoro-m-toluidino)pyrrol-2-yl1oxamic acid, THAM salt (Ia),(3-cyano-4-methyl-l-propylpyrrol-Z-yl)oxamic acid, 5

THAM salt (Ia), [3-cyano-4-methyl- 1 (m-chloroanilino pyrrol-2-yl]oxamic acid, THAM salt (Ia),[3-cyano-4-methyl-1-(o-methoxyanilino)pyrrol-Z-yl] oxamic acid, THAMsalt (Ia), [3-cyano-4-methyl- 1- (p-methylanilino) pyrrol-Z-yl] oxamicacid, THAM salt (Ia),[3-cyano'4methyl-1-(a,a,a-trifiuoro-o-toluidino)pyrrol-2- yl] oxamicacid, sodium salt (Ia),(3-cyano-4-methyl-5-ethyl-1-pentylpyrrol-2-yl)oxamic acid, THAM salt(Ia), (3-cyano-4-methyl-5-ethylpyrro1-2-yl]oxamic acid, THAM salt (Ia),[3-cyano-4-methyl-5-ethyl-1-(m-chloroanilino)pyrrol-2- yl]oxamic acid,THAM salt (Ia),[3-cyano-4-methyl-5-ethyl-1-(p-fiuoroanilino)pyrrol-2-yl] oxamic acid,calcium salt (Ia),[3-cyano-4-methyl-5-ethyl-1-(o-methoxyanilino)pyrrol-2- yl]oxamic acid,THAM salt (Ia), [3-cyano-4-methyl-5-ethyl-l-(m-methylanilino)pyrrol-Z-yl]oxamic acid, THAM salt (Ia),3-cyano-4-methyl-5-propyll-propylpyrrol-Z-yl) oxamic acid, THAM salt(Ia), [3-cyano-4-methyl-5-propyl-1-(o-bromoanilino)pyrrol-2- yl]oxamicacid, THAM salt (Ia),[3-cyano-4-methyl-5-propyl-l-(p-methoxyanilino)pyrrol- 2-yl]oxamic acid,sodium salt (Ia),[3-cyano-4-methyl-5-propyl-l-(m-methylanilino)pyrrol-Z- yl]oxamic acid,THAM salt (Ia),

etc.

What is claimed is: 1. A compound of the formula carbon atoms,

wherein X is selected from the group consisting of hydrogen, fluorine,chlorine, bromine, methoxy, methyl, and trifluoromethyl, R is selectedfrom the group consisting of hydrogen and lower alkyl of 1 through 6carbon atoms, and R has the same meaning as R and in addition hydrogen.

2. A compound of claim 1 wherein M is sodium, R and R are methyl, and Ris hydrogen, namely, (3-cyano-4,5- dimethylpyrrol-Z-yl)oxamic acid,sodium salt.

3. A compound of claim 1 wherein M is hydrogen, R is wherein X ishydrogen and R and R are hydrogen, namely,(3-cyano-4-phenylpyrrol-2-yl)oxamic acid.

4. A compound of claim 1 wherein M is hydrogen, R is Wherein X ishydrogen, R is methyl, and R is hydrogen, namely, (3-cyano 5methyl-4-phenylpyrrol-2-yl)oxamic acid.

5. A compound of claim 1 wherein M is hydrogen, R and R are methyl and Ris wherein X is hydrogen, namely, (3-cyano-4,5-dimethyl-1-phenylpyrrol-2-yl)oxamic acid.

References Cited Theilheimer, Synthetic Methods of Organic Chemistry,vol. 16 (1962), p. 235, #502.

JOSEPH A. NARCAVAGE, Primary Examiner US. Cl. X.R.

V iColumn 2, l ine 5, al ky" should read al kyl" erline 6, "My" shouldread --N line 45, "of 2-amlno-" should read of a 2-amino- Column 4, line15, should read H "X'E-COR" --X'CCOR-; Column 7, line 1, "-cyano-.,4-"should read cyanol ines 1-2, "phenylpyrole" should read--phenylpyrrole--;

lines 14-15, "material), should read --material,--; Column 9,

6 line 4, 5-amino-" should read 2-aminoline 9, "(p-ethyl) UNITED STATESPATENT oTTTcE Page 1of 2 CERHHCATE e1 CURRECHQN Patent No. 53 5 35 DatedSeptember 17, 1974- Inventor(s) Herbert G. Johnson, John B Wright,Charles M, Hal l,

and Donald T. Warner It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 5,

should read --(p-methyl-)--; line 15, "Bully." should read --Bull.--;Column 10, line 70, "5"" should read 5- Column 11, line 57, 'yl[ shouldread --yl]--; line 61, "yl[" should read --yl]--; line 65, "yl[' shouldread --yl]--; line 69, '"yl[" should read l]--; Column 12, line 1, "-5should read "4-- l ine 2, "yl should read -yl]--; l ine 6, "yl[' shouldread --yl]-; line 55, "2cyano-" should read (5-cyanoline 59, "and and 20of" should read and 20 ml of"; l ine 56, yrryl oxamate" should readyrryl)oxamate--; Column 15, line 5, "4,5 diethyl" should read,5-diethyl--; Column 18, line 68, "[prepared" should read --(prepared--;line 69, "856]" should read --856)--; l ine 70, "[prepared" should read--(prepared--; 1 ine 7l, "6824]" should read 6824) line 74, "[prepared"should read (prepa red-; l ine 75, "2544]" should read --2544)-- Column19, line 1, "[prepared" should read "(prepared-w line 1, "5599]" shouldread --5599)--; line 2, "[prepared" should read --(prepared--; line 5,"494]" should read --494)--; line 4, "[prepared" should read--(prepared--; line 5, "955]" should read --955)--; line 6,"[prepared"should read ---(prepared--;

1 ine 7, "255]" should read -255)--; line 8, "[prepared" should read--(prepared--; line 9, 1015]" should read 1015)--; line 12, "[prepared"should read --(prepared--; line 15, "2469]" should read --2469)--;Column 20, line 5, "-2- should read 2-yl l ine 40, fluoranl l ine"should read fl ili g UNITED STATES PATENT OFFICE Page 2 of Z CE'HHCATE=1 Patent No. 5,856,541 Dated September 17, 1974 b Inventor(s) HerbertG. Johnson, John B. Wright, Charles M. Hall,

' and Donald T. Warner It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

qfiolumn 22, l ine 24, "sweeteners" should read --sweetners-- l ine 565, "aluminium" should read --aluminum--; line 7'2, M-aluminum" shouldread --M=a luminum"; l ine 72, "sodium" should read --sodium,--; Column25, line 9, "as" should read --at--; line 46, "0,1" should read--0.0l--; l ine 66, "for" should read --or--; line 75, "condiitons"should read --conditions--; Column 27,

line 17', "[3" should read "(5- line 17, "yll" should read Q--yl)--;Column 29, lines ll-45, formula la,

11 R1 H R1 i I should read R2 -N-C- C-OM R2 b N H ll ii i 0 0 3 Signedand Sealed this a Seventeenth 3) 0f April 1979 [SEAL] I Arrest:

' DONALD w. BANNER RUTH C. MASON Anestiag Officer Comn'lissioaer ofPatents and Trademarks

